Therapeutic method of stimulating digestive tract contractile motion in mammals

ABSTRACT

Disclosed are digestive tract contractile motion stimulants containing compounds, or salts thereof, represented by the following general formula: ##STR1## The compounds described above have an excellent effect of stimulating the gastrointestinal contractile motion, and the preparation of the present invention containing these compounds can be advantageously used as digestive tract contractile motion stimulants.

The present invention relates to a stimulant for contractile motion ofthe digestive tract of mammals.

PRIOR ART

The digestive tract consists of the stomach, the duodenum, the smallintestine, etc., and plays an important role in the digestion of foodtaken from the mouth. The contructile motion of the digestive tract isessential in order to perform the digestion smoothly. In a healthy man,the autonomous nerve system and digestive tract hormones functioneffectively to induce contraction of the digestive tract not onlyimmediately after the intake of foods but also in a state where thedigestive tract is empty, when such contraction has been consideredabsent. The movement in such empty digestive tract is transmitted fromthe stomach to the duodenum and to the small intestine, and plays animportant role for cleaning the digestive tract, thus preparing for nextintake of foods (Z. Itoh, "Iden", 33, 29, 1979).

A stimulant for contraction of the digestive tract is expected to inducea normal movement of the digestive tract, in a human with weakenedfunction of the digestive tract, thereby a healthy body beingmaintained.

Motilin is already known as a digestive tract hormone for stimulatingthe contraction of the digestive tract. This substance is a peptide,consisting of 22 amino acids and extracted by J. C. Brown in 1966 fromthe mucous membrane of a pig duodenum (J. C. Brown et al.,Gastroenterology, 50, 333, 1966), and is already synthesized chemically(E. Wunsch et al., Zeitschrift fur Naturfoisch, 28C, 235, 1973).

PROBLEM TO BE RESOLVED BY THE PRESENT INVENTION

However the supply of motilin by extraction from natural substance or bychemical synthesis is not sufficient, and has not been possible in alarge amount.

MEANS FOR SOLVING THE PROBLEM

In the course of a survey for providing a substance capable ofstimulating the contraction of the digestive tract and adapted for alarge supply, the present inventors have synthesized various derivativesfrom antibiotic erythromycin A, B, C, D and F and have found that saidderivatives have a strong stimulating effect on the contraction of thedigestive tract.

Based on this finding, the present inventors have made intensive effortsand have reached the present invention.

The present invention provides:

A digestive tract contractile motion stimulant containing a compound, ora salt thereof, represented by the general formula: ##STR2## wherein R¹stands for a hydrogen atom or an acyl radical which may be substituted;R² stands for a hydrogen atom, an acyl or alkyl radical which may besubstituted; R³ stands for a hydrogen atom or a methyl radical; R⁴stands for a hydrogen atom or a hydroxy radical; R^(a) stands for theformula ##STR3## wherein R^(b) stands for a hydrogen atom, a lower alkylor cycloalkyl radical, R^(c) stands for a hydrogen atom, a lower alkyl,cycloalkyl, lower alkenyl or lower alkynyl radical which may besubstituted, or R^(b) and R^(c) form a cyclic alkylamino radicaltogether with the adjacent nitrogen atom) or the formula ##STR4##(wherein R^(d) stands for a lower alkyl radical, each of R^(e) andR^(f), which may be the same or different, stands for a lower alkyl,cycloalkyl, lower alkenyl or lower alkynyl radical which may besubstituted, or R^(e) and R^(d) form a cyclic alkylamino radicaltogether with the adjacent nitrogen atom, and X⁻ stands for an anion);and when R^(a) is the formula ##STR5## stands for the formula: ##STR6##wherein, Z stands for the formula ##STR7## (wherein R⁵ stands for ahydrogen atom, an acyl or alkyl radical which may be substituted, and R⁶stands for a hydrogen atom, an acyl radical of a lower carboxylic acidor an alkyl radical which may be substituted by an alkylthio radical),the formula ##STR8## (wherein R⁷ stands for a hydrogen atom, an acyl oralkyl radical which may be substituted), ##STR9## (wherein Y stands forthe formula B--R⁸ wherein R⁸ stands for an alkyl or aryl radical,##STR10## or the formula ##STR11## wherein each of R⁹ and R¹⁰, which maybe the same or different, stands for a hydrogen atom or an alkylradical, or constitutes a cyclic alkyl radical with the adjacent carbonatom, or either of R⁹ and R¹⁰ is a hydrogen atom, an alkyl radical or anaryl radical while the other is a dialkylamino radical), R¹¹ and R¹²both stand for hydrogen atoms or both taken together form a chemicalbond, or the formula: ##STR12## wherein Z' stands for the formula##STR13## (wherein R¹³ stands for a hydrogen atom, an acyl or alkylradical which may be substituted), or when R^(a) is the formula##STR14## stands for the formula: ##STR15## wherein R¹¹, R¹² and Z havethe same meanings as defined above, the formula: ##STR16## wherein Z'has the same meaning as defined above, or the formula: ##STR17## whereinZ has the same meaning as defined above, and R⁰ stands for a hydrogenatom or low alkyl; with proviso that each of R¹, R², R⁴, R⁵, and R⁶ isnot a hydrogen atom at the same time, when R^(a) is a dimethylaminoradical, both of R¹¹ and R¹² taken together form a chemical bond and R³is a methyl radical; and each of R¹, R², R⁴ and R¹³ is not a hydrogenatom at the same time, when R^(a) is a dimethylamino radical and R³ is amethyl radical.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The acyl radical represented by R¹ in the foregoing formula can be acarboxylic acyl, a sulfonic acyl, a phosphorous acyl or a phosphoricacyl.

The acyl radical represented by R², R⁵ or R⁷ in the foregoing formulacan be a carboxylic acyl or a sufonic acyl.

The carboxylic acyl is an acyl radical derived from a carboxylic acid,which can be a monocarboxylic or polycarboxylic acid, and a saturated orunsaturated carboxylic acid.

As the monocarboxylic acyl radical, a saturated or unsaturated acylradical containing 1 to 20 carbon atoms (such as formyl, acetyl,propionyl, butyryl, isobutyryl, valeryl, isovaleryl, hexanoyl, pivaloyl,lauroyl, myristoyl, palmitoyl, stearoyl, acryloyl, propioloyl,methacryloyl etc.) or an aryl carboxylic acyl radical are preferred. Thearyl carboxylic acid include benzene carboxylic acid, naphthalenecarboxylic acid and the like.

As the polycarboxylic acyl radical, a dicarboxylic acyl radical, whichcan be a saturated or unsaturated acyl radical containing 2 to 6 carbonatoms, which may optionally be esterified, such as oxalo, carboxyacetyl,3-carboxypropionyl, cis-3-carboxyacryloyl, trans-3-carboxyacryloyl,cis-3-methyl-3-carboxyacryloyl, etc, are preferred.

The sulfonic acyl is an acyl radical derived from a sulfonic acid,represented for example by the general formula R¹⁴ SO₂ - wherein R¹⁴stands for an alkyl, aryl or aralkyl radical. The alkyl radicalpreferably contains for example 1 to 6 carbon atoms, and may be linearor branched. Examples of the alkyl radicals are methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl and n-hexyl.Examples of the aryl radical include phenyl and naphthyl. The arylradical may have a substituent and examples of said substituent includea lower alkyl radical (such as methyl), a lower alkoxy radical (such asmethoxy), a halogen atom (such as fluorine, chlorine, and bromine), anitro radical, a carboxy radical, etc.

An example of said aralkyl is 2-phenethyl.

The phosphrous acyl is an acyl radical derived from phosphorous acid,represented, for example, by the general formula ##STR18## wherein R¹⁵stands for a hydrogen atom, an alkyl, aryl or aralkyl radical. The alkylradical preferably contains for example, 1 to 6 carbon atoms and can belinear or branched. Examples of the alkyl radicals include methyl,ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl,n-pentyl and n-hexyl. Examples of the aryl radical include phenyl, tolyland naphthyl.

The aralkyl radical can be an aryl alkyl radical, wherein the aryl canbe the above-mentioned aryl, while the alkyl preferably contains 1 to 3carbon atoms, and there can be mentioned, for example, methyl, ethyl orpropyl.

The phosphoric acyl is an acyl radical derived from phosphoric acid,represented, for example, by a general formula (R¹⁶ O)₂ PO- wherein R¹⁶has the same meaning as R¹⁵. The substituent in the acyl radical whichmay be substituted, represented by R¹, R², R⁵ and R⁷, can be, forexample, a halogen atom, an alkoxy or alkylthio radical.

Examples of the halogen atoms are chlorine, bromine, fluorine andiodine.

As the alkoxy radical, there can be mentioned radicals containing 1 to 4carbon atoms, such as methoxy, ethoxy, propoxy and butoxy.

As the alkylthio radical, there can be metioned radicals containing, 1to 4 carbon atoms, such as, methylthio, ethylthio, propylthio,isopropylthio, butylthio, isobutylthio, sec-butylthio andtert-butylthio.

The lower carboxylic acyl radical represented by R⁶ in the foregoingformula can be a monocarboxylic acyl or polycarboxylic acyl radicalcontaining 1 to 6 carbon atoms, such as, formyl, acetyl, propionyl,butyryl, isobutyryl, valeryl, isovaleryl, hexanoyl, oxalo, carboxyacetylor 3-carboxypropionyl.

In the foregoing formula, the alkyl radical in the alkyl radical whichmay be substituted, represented by R⁰, R², R⁵ or R⁷, preferably contains1 to 3 carbon atoms, and can be linear or branched. Examples of thealkyl radicals include methyl, ethyl, propyl and isopropyl. Thesubstituent is preferably an alkoxy radical containing 1 to 3 carbonatoms or an alkoxyalkoxy radical containing 2 to 6 carbon atoms, andexamples of the alkoxy radicals include methoxy, ethoxy and propoxy,while examples of the alkoxyalkoxy radicals include methoxyethoxy,methoxypropoxy, methoxybutoxy, methoxypentyloxy, ethoxyethoxy,ethoxypropoxy, ethoxybutoxy and propoxypropoxy.

In the foregoing formula, the alkyl radical which is represented by R⁶and may have an alkylthio substituent can be methyl. The alkylthio asthe substituent may include a radical represented by the general formula##STR19## wherein R¹⁷ is a lower alkyl radical. The lower alkyl radicalpreferably contains 1 to 3 carbon atoms, such as methyl, ethyl orpropyl.

In the foregoing formula, the alkyl radical represented by R⁸ maycontain 1 to 6 carbon atoms, preferably 1 to 3 carbon atoms, andexamples thereof include methyl, ethyl and propyl.

In the foregoing formula, the aryl radical represented by R⁸ is, forexample, phenyl, tolyl or naphthyl.

In the foregoing formula, the alkyl radical containing 1 to 6 carbonatoms, represented by R⁹ and R¹⁰, can be linear or branched, andexamples thereof include methyl, ethyl, propyl, isopropyl, butyl,isobutyl, sec-butyl, tert-butyl, n-pentyl and n-hexyl. Among thesepreferred is a linear or branched radical containing 1 to 3 carbonatoms, such as methyl, ethyl, propyl or isopropyl.

In the foregoing formula, the carbon chain represented by R⁹ and R¹⁰ forforming a cyclic alkyl together with the carbon atom in the acetal bondmay have 4 to 5 carbon atoms, including tetramethylene, pentamethylene,etc.

In the foregoing formula, the aryl radical represented by R⁹ and R¹⁰ is,for example, phenyl, tolyl or naphthyl.

In the foregoing formula, the dialkylamino radical represented by R⁹ andR¹⁰ is represented by the general formula --N(R¹⁸)₂, wherein R¹⁸ standsfor a lower alkyl radical The lower alkyl radical may contain 1 to 3carbon atoms, such as methyl, ethyl or propyl.

In the foregoing formula, the lower alkyl radical represented by R^(b)or R^(d) contains preferably 1 to 6 carbon atoms and examples thereofinclude methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,pentyl, isopentyl and hexyl.

As to R^(a) in the foregoing formula, the lower alkyl radicalrepresented by R^(e) or R^(f) which may have substituents containspreferably 1 to 6 carbon atoms, and examples thereof include methyl,ethyl, propyl, isopropyl, butyl, isobutyl, pentyl and hexyl.

In the foregoing formula, substituted or unsubstituted cycloalkylrepresented by R^(b), R^(e) or R^(f) may contain 3 to 7 carbon atoms,and examples thereof include cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, preferably those having 4 to 6 carbon atoms,namely cyclobutyl, cyclopentyl and cyclohexyl.

The lower alkenyl radical which may be substituted, represented by R^(e)or R^(f), contains preferably 2 to 6 carbon atoms, and examples thereofinclude vinyl, allyl, 2-butenyl, methylallyl, 3-butenyl, 2-pentenyl,4-pentenyl, and 5-hexenyl.

The lower alkynyl radical which may be substituted, represented by R^(e)or R^(f), contains preferebly 2 to 6 carbon atoms, and examples thereofinclude ethynyl, propargyl, 2-butyn-1-yl, 3-butyn-1-yl, 3-butyn-2-yl,1-pentyn-3-yl, 3-pentyn-1-yl, 4-pentyn-2-yl, and 3-hexyn-1-yl.

The substituents in the foregoing alkyl, cycloalkyl, alkenyl and alkynylradicals, each of which may be substituted, include, for example,hydroxy, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, C₁₋₄ alkoxy, C₁₋₄ alkoxy-C₂₋₃-alkyl, C₃₋₆ cycloalkyloxy, C₆₋₁₀ aryloxy, C₇₋₁₂ aralkyloxy, C₁₋₄alkylthio, C₃₋₆ cycloalkylthio, C₆₋₁₀ arylthio, C₇₋₁₂ aralkylthio,amino, monoC₁₋₄ alkylamino, diC₁₋₄ alkylamino, C₃₋₆ cycloalkylamino,C₆₋₁₀ arylamino, C₇₋₁₂ aralkylamino, azido, nitro, halogen, cyano,carboxy, C₁₋₄ alkoxycarbonyl, C₆₋₁₀ aryloxycarbonyl, C₃₋₆cycloalkyloxycarbonyl, C₇₋₁₂ aralkyloxycarbonyl (CO in these carbonylgroups may be acetalyzed) C₁₋₅ alkanoyl, formyloxy, C₁₋₄ alkylsulfinyl,C₆₋₁₀ arylsulfinyl, C₁₋₄ alkylsulfonyl, C₆₋₁₀ arylsulfonyl, C₁₋₁₅alkanoyloxy, sulfo, carbamoyl, carbamoyl which may be substituted,carbamoyloxy, carbamoyloxy which may be substituted, formylamino, C₁₋₄alkanoylamino, C₆₋₁₀ arylcarbonylamino, C₁₋₄ alkoxycarbonylamino, C₇₋₁₂aralkyloxycarbonylamino, oxo, epoxy, thioxo, sulfonamido, heterocyclicradical, heterocyclic thio, heterocyclic carbonylamino, heterocyclicoxy, heterocyclic amino, C₁₋₄ alkoxycarboxycarbonyloxy, C₁₋₄alkylsulfonyloxy, C₆₋₁₀ arylsulfonyloxy, sulfoamino, sulfamoylamino,ureido, and silyloxy.

The alkyl having cycloalkyl, aryl, C₁₋₄ alkyl and the alkyl having agroup containing heterocyclic radical, which may substitute to alkyl,alkenyl, alkynyl or cycloalkyl mentioned above, may have furthersubstituents. Examples of such substituents are hydroxy, C₁₋₄ alkyl(which may have substituents, and the substituent in this case is thesame as the substituents in the alkyl as described above; the radicalcontaining C₁₋₄ alkyl as hereinafter mentioned may also have the samesubstituent), C₁₋₄ alkoxy, C₁₋₄ alkylthio, amino, C₁₋₄ alkylamino,diC₁₋₄ alkylamino, C₆₋₁₀ arylamino, azido, nitro, halogen, oxo, cyano,carboxy, C₁₋₄ alkoxycarbonyl, C₆₋₁₀ aryloxycarbonyl, C₁₋₅ alkanoyl, C₁₋₅alkanoyloxy, sulfo, carbamoyl, substituted carbamoyl, carbamoyloxy, C₁₋₄alkanoylamino, C₁₋₄ alkoxycarbonylamino and sulfonamido.

Examples of the substituent in the foregoing aryl and heterocyclicradicals which may substituted include hydroxy, C₁₋₄ alkyl, C₆₋₁₀ aryl,C₃₋₆ cycloalkyl, halogen, carboxy, sulfo, C₁₋₄ alkoxy, C₁₋₄ alkylthio,nitro, C₁₋₄ alkoxycarbonyl, amino, monoC₁₋₄ alkylamino, diC₁₋₄alkylamino, C₁₋₄ alkanoylamino, C₆₋₁₀ aryloxy, C₇₋₁₂ aralkyl, C₇₋₁₂aralkyloxy, C₆₋₁₀ arylamino, C₇₋₁₂ aralkylamino, cyano, C₆₋₁₂aryloxycarbonyl, C₇₋₁₂ aralkyloxycarbonyl, C₁₋₅ alkanoyl, C₁₋₅alkanoyloxy, carbamoyl, carbamoyl which may be substituted,carbamoyloxy, which may be substituted, C₁₋₄ alkoxycarbonyl- amino andoxo.

The alkyl, the radical containing C₁₋₄ alkyl or the aryl group which isthe substituent in the foregoing aryl and heterocyclic radical which maybe substituted may further have substituents, and as the substituentsthe same substituents as the alkyl and aryl radicals as described abovemay be included.

The number of the substituents on the foregoing respective radicals ispreferably 1 to 3.

These substituents will be described in detail below.

Examples of C₁₋₄ alkyl radical as the substituent include methyl, ethyl,propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl

Examples of C₃₋₆ cycloalkyl radicals include cyclopropyl, cyclobutyl,cyclopentyl and cyclohexyl

Examples of C₆₋₁₀ aryl radicals include phenyl and naphtyl.

Examples of C₁₋₄ alkoxy radical include methoxy, ethoxy, propoxy,isopropoxy, butoxy and tert-butoxy.

Examples of C₃₋₆ cycloalkyloxy radicals include cyclopropyloxy,cyclopentyloxy and cyclohexyloxy

Examples of C₆₋₁₀ aryloxy redicals include phenoxy and naphtyloxy.

Examples of C₇₋₁₂ aralkyloxy redical include benzyloxy, 2-phenethyloxyand 1-phenethyloxy

Examples of C₁₋₄ alkylthio radicals include methylthio, ethylthio,propylthio and butylthio.

Examples of C₃₋₆ cycloalkylthio radicals include cyclopropylthio,cyclopentylthio and cyclohexylthio.

Examples of C₆₋₁₀ arylthio radical include phenylthio and naphtylthio.

Examples of C₇₋₁₂ aralkylthio radicals include benzylthio,2-phenethylthio and 1-phenethylthio.

Examples of monoC₁₋₄ alkylamono radicals include methylamino,ethylamino, propylamino, isopropylamino, butylamino, isobutylamino andtert-butylamino.

Examples of diC₁₋₄ alkylamino radicals include dimethylamino,diethylamino, dipropylamino, dibutylamino, N-methyl-N-ethylamino,N-methyl-n-propylamino and N-methyl-N-butylamino.

Examples of C₃₋₆ cycloalkylamino radicals include cyclopropylamino,cyclobutylamino, cyclopentylamino and cyclohexylamino.

Examples of C₆₋₁₀ arylamino radicals include anilino and the like.

Examples of C₇₋₁₂ aralkylamino radicals include benzylamino,2-phenethylamino and 1-phenethylamino.

Examples of halogen atoms include fluorine, chlorine, bromine andiodine.

Examples of C₁₋₄ alkoxycarbonyl radicals include methoxycarbonyl,ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl,tert-butoxycarbonyl and isobutoxycarbonyl.

Example of C₆₋₁₀ aryloxycarbonyl radicals include phenoxycarbonyl andthe like.

Examples of C₃₋₆ cycloalkyloxycarbonyl radicals includecyclopropyloxycarbonyl, cyclobutyloxycarbonyl, cyclopentyloxycarbonyland cyclohexyloxycarbonyl.

Examples of C₇₋₁₂ aralkyloxycarbonyl radicals include benzyloxycarbonyl,1-phenetyloxycarbonyl and 2-phenetyloxycarbonyl.

Examples of C₁₋₅ alkanoyl radicals include formyl, acetyl, propionyl,butyryl and pivaloyl.

Examples of C₁₋₁₅ alkanoyloxy radicals include formyloxy, acetoxy,butyryloxy, pivaloyloxy, pentanoyloxy, hexanoyloxy, heptanoyloxy,octanoyloxy, nonanoyloxy, decanoyloxy, undecanoyloxy, dodecanoyloxy,tridecanoyloxy, tetradecanoyloxy and pentadecanoyloxy.

Examples of substituted carbamoyl radicals include N-methylcarbamoyl, N,N-dimethylcarbamoyl, N-ethylcarbamoyl, N, N-diethylcarbamoyl,N-phenylcarbamoyl, pyrrolidinocarbonyl, piperidinocarbonyl,piperazinocarbonyl, morpholinocarbonyl and N-benzylcarbamoyl.

Examples of substituted carbamoyloxy radicals includeN-methylcarbamoyloxy, N, N-dimethylcarbamoyloxy, N-ethylcarbamoyloxy,N-benzylcarbamoyloxy, N, N-dibenzylcarbamoyloxy, N-benzylcarbamoyloxy,N, N-dibenzylcarbamoyloxy and N-phenylcarbamoyloxy.

Examples of C₁₋₄ alkanoylamino radicals include formylamino, acetamido,propionamido and butyrylamino.

Example of C₆₋₁₀ arylcarbonylamino radicals include benzamido and thelike.

Examples of C₁ alkoxycarbonylamino radicals includemethoxycarbonylamino, ethoxycarbonylamino, butoxycarbonylamino andtert-butoxycarbonylamino.

Examples of C₇₋₁₂ aralkyloxycarbonylamino radical includebenzyloxycarbonylamino, 4-methoxybenzyloxycarbonylamino,4-nitrobenzyloxycarbonylamino and 4-chlorobenzyloxycarbonylamino.

Examples of sulfonamido radicals include methanesulfonylamino,ethanesulfonylamino, butanesulfonylamino, benzenesulfonylamino,toluenesulfonylamino, naphtalenesulfonylamino,trifuluoromethanesulfonylamino, 2-chloroethanesulfonylamino and2,2,2-trifuluoromethanesulfonylamino.

Heterocyclic radicals include cyclic groups containing 1 to 5 nitrogenatoms, oxygen atoms, sulfur atoms and examples thereof are pyrrolidinyl,pyrrolyl, pyrazolyl, imidazolyl, furyl, thienyl, oxazolyl, isooxazolyl,isothiazolyl, thiazolyl, piperidinyl, pyridyl, pyridazinyl, pyrazinyl,piperadinyl, pyrimidinyl, pyranyl, tetrahydropyranyl, tetrahydrofuryl,indolyl, quinolyl, 1,3,4-oxadiazolyl, thieno[2,3-d]pyridyl,1,2,3-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl,1,2,4-triazolyl, 1,3,4-triazolyl, tetrazolyl, 1,3-dioxoranyl,tetrazolo[1,5b]pyridazinyl, benzothiazolyl, benzooxazolyl,benzoimidazoryl, benzothienyl and morpholinyl.

As a heterocyclic thio, heterocyclic oxy, heterocyclic amino andheterocyclic carbonylamino radicals, there can be mentioned radicalshaving the above heterocyclic radicals bonded to sulfur atom, oxygenatom, nitrogen atom or carbonylamino radical, respectively.

Examples of C₁₋₄ alkylsulfonyloxy radicals include methanesulfonyloxy,ethanesulfonyloxy and butanesulfonyloxy.

Examples of C₆₋₁₀ arylsulfonyloxy radicals include benzenesulfonyloxyand toluenesulfonyloxy.

Examples of silyloxy radicals include trimethylsilyloxy,t-butyldimethylsilyloxy and t-butyldiphenylsilyloxy.

Examples of C₁₋₄ alkylsulphynyl radicals include methylsulfinyl,ethylsulfinyl, propylsulfinyl and butylsulfinyl.

Examples of C₆₋₁₀ arylsulfinyl radicals include phenylsulfinyl andnaphtylsulfinyl.

Examples of C₁₋₄ alkylsulfonyl radicals include methanesulfonyl,ethanesulfonyl and butanesulfonyl.

Examples of C₆₋₁₀ arylsulfonyl radicals include benzenesulfonyl andtoluenesulfonyl.

Examples of C₁₋₄ alkoxycarbonyloxy radicals include methoxycarbonyloxy,ethoxycarbonyloxy and tert-butoxycarbonyloxy.

Further specific examples of the foregoing respective radicals includechloromethyl, bromomethyl, iodomethyl, trifluoromethyl, chloroethyl,bromoethyl, iodoethyl, chloropropyl, hydoroxymethyl, hydroxyethyl,hydroxypropyl, 2-hydroxy-2-phenylethyl, cyclopropylmethyl,cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl,2-cyclohexylethyl, 3-chlorocyclobutylmethyl, benzyl, 4-chlorobenzyl,4-nitrobenzyl, 4-methoxybenzyl, 2,4-dimethoxybenzyl,3,4-dimethoxybenzyl, 4-methylbenzyl, 2-ethoxyethyl,2-(2,2,2-trifuluoroethoxy)ethyl, methoxymethyl, 2,2-dimethoxyethyl,2,2-diethoxyethyl, cyclopropylmethoxymethyl, cyclobutylmethoxymethyl,2-cyclopropylmethoxyethyl, 2-cyclobutylmethoxyethyl, 2-benzyloxyethyl,3-benzyloxypropyl, 2-phenoxyethyl, 2-(2-phenethoxy)ethyl,3-phenylpropyl, methylthiomethyl, 2-methylthioethyl, 2-phenylthioethyl,2-benzylthioethyl, 2-butylthioethyl, cyclohexylthiomethyl,2-(4-pyridylthio)ethyl, aminomethyl, aminoethyl, 2-methylaminoethyl,2-tert-butylaminoethyl, 2-dimethylaminoethyl, 3-dimethylaminopropyl,2-cyclohexylaminoethyl, 2-benzylaminoethyl, 2-azidoethyl, nitromethyl,2-nitroethyl, cyanomethyl, 2-cyanoethyl, 4-cyanobutyl, carboxymethyl,2-carboxyethyl, ethoxycarbonylmethyl, phenoxycarbonylmethyl,cyclopentyloxycarbonylmethyl, acetylmethyl, benzoylmethyl,4-chlorobenzoylmethyl, 3-(4-bromobenzoyl)propyl, 3-methoxybenzoylmethyl,2-formyloxyethyl, 2-methylsulfinylethyl, 2-phenylsulfinylethyl,2-methylsulfonylethyl, 3-phenylsulfonylpropyl, 2-acetoxyethyl,4-acetoxybutyl, pivaloyloxymethyl, 3-sulfopropyl, carbamoylmethyl,3-carbamoylpropyl, pyrrolidinocarbonylmethyl,2-(N-ethyl-benzylamino)ethyl, 2-(2-oxopyrrolidino)ethyl,2-formylaminoethyl, 3-formylaminopropyl, 3-trifluoroacetamidopropyl,2-benzamidoethyl, 3-tert-butoxycarbonylaminopropyl,benzyloxycarbonylaminopropyl, 2,3-epoxypropyl, 2-thioacetamidoethyl,3-sulfoaminopropyl, 2-(1,3-dioxoran-2-yl)ethyl, 2-,3-, 4-pyridylmethyl,2-(4-pyridyl)ethyl, 3-(4-pyridyl)propyl, furfulyl, 3-(2-furyl)allyl,3-(2-furyl)propyl, 2-(2pyranyloxy)ethyl, 2-(3-indolyl)ethyl,3-(1-indolyl)propyl, 3-(2-benzimidazolyl)propyl, 2-morpholinoethyl,(3-isoxazolyl)methyl, 2-(2-pyridylthio)ethyl, 2-(2-benzthiazolyl)ethyl,2-(2-pyrimidinylthio)ethyl, 2-(2-aminoethylthio)ethyl,2-isonicotinoylaminoethyl, 2-thenoylaminoethyl, 2-furoylaminoethyl,2-(tert-butoxycarbonyloxy)ethyl, 3-(tert-butoxycarbonyloxy)propyl,2-methylsulfonyloxyethyl, 2-(p-toluenesulfonyloxy)ethyl,2-(tert-butyldimethylsilyloxy)ethyl, sulfoaminomethyl,2-(sulfoaminoethyl, ureidomethyl, 2-ureidoethyl, sulfamoylaminomethyl,2-sulfamoylaminoethyl and (2-methoxyethoxy)methyl.

Examples of more preferable substituents in the lower alkyl, cycloalkyl,lower alkenyl and lower alkynyl readicals which may be substitutedinclude halogen atoms (such as chlorine, bromine, iodine and fluorine),lower alkoxy groups having 1 to 4 carbon atoms (such as methoxy, ethoxy,propoxy, isoprooxy, and butoxy), lower alkylthio radicals having 1 to 4carbon atoms (such as methylthio, ethylthio, propylthio, and butylthio),aryl radicals (such as phenyl, tolyl, naphthyl, etc.), hydroxyl radical,alkoxycarbonyloxy radicals (such as tert-butoxycarbonyloxy),aralkyloxycarbonyloxy radicals (such as benzyloxycarbonyloxy), amino,substituted amino radicals (such as dimethylamino, and diethylamino),heterocyclic radicals (cyclic amino) (such as morpholino, piperidino,pyrrolidino, and 2-oxypyrrolidino), acyloxy radicals having 1 to 3carbon atoms (such as formyloxy acetoxy and trifluoroacetoxy), acylaminoradicals having 1 to 3 carbon atoms (such as acetamido, andtrifluofroacetamido), carboxy, lower (C₁₋₄) alkoxycarbonyl radicals(such as methoxycarbonyl, ethoxycarbonyl, and butoxycarbonyl),carbamoyl, substituted carbamoyl radicals (such as dimethylcarbamoyl anddiethylcarbamoyl), sulfo and others.

In the foregoing formula, as the carbon chain represengted by R^(b) andR^(c) or R^(d) and R^(e) for forming a nitrogen containing cyclicalkylamino together with the nitrogen atom on the 3'-position, thosehave 3 to 6 carbon atoms such as trimethylene, tetramethylene,pentamethylene and hexamethylene are included.

In the foregoing formula, examples of the anions represented by X⁻include halogen ions (such as iodide ion, bromo ion and chloro ion),sulfate ion, phosphate ion, nitrate ion, methanesulfate ion,p-tolylsulfate ion, benzenesulfate ion, hydroxyl ion and organiccarboxylae ion (such as oxalate ion, maleate ion, fumarate ion,succinate ion, citrate ion, lactate ion, trifluoroacetate ion,lactobionate ion, acetate ion, propinate ion and ethylsuccinate ion).

In the compound (1) of the present invention, it is preferable that R⁰is a hydrogen atom; R¹ is a hydrogen atom or an alkyl carboxylic acylradical having 1 to 5 carbon atoms; R² is a hydrogen atom, an alkylcarboxylic acyl radical having 1 to 5 carbon atoms, an alkyl sulfonicacyl radical having 1 to 5 carbon atoms; or an alkylthiomehyl radicalhaving 1 to 5 carbon atoms; R³ is a methyl radical; R⁴ is a hydrogenatom; Z is the formula ##STR20## wherein each of R⁵ and R⁶ is a hydrogenatom, an alkyl carboxylic acyl radical having 1 to 5 carbon atoms or analkyl sulfonic acyl radical having 1 to 5 carbon atoms, or R⁵ and R⁶from ##STR21## as Y; each of R^(d) and R^(e) is an alkyl radical having1 to 3 carbon atoms, or R^(d) and R^(e) form a cyclic alkyl radical;R^(f) is an unsubstituted or substituted alkyl radical having 1 to 5carbon atoms, a alkenyl or alkynyl radical having 2 to 6 carbon atoms.

It is further preferable that at least one of R⁵ and R⁶ is an alkylcarboxylic acyl or alkylthiomethyl radical, each of which has 1 to 5carbon atoms, or Y is ##STR22## when R^(d) and R^(e) are alkyl radicalshaving 1 to 3 carbon atoms and form a tertiary amino radical as R^(a),and each of R¹ and R² is an hydrogen atom or an alkyl carboxylic acylhaving 1 to 5 carbon atoms. Furthermore, at least one of R⁵ and R⁶ ispreferably an alkyl carboxylic acyl radical having 1 to 5 carbon atoms,an alkylthiomethyl radical having 1 to 5 carbon atoms or an alkylsulfonic acyl radical having 1 to 5 carbon atoms, or Y is preferably##STR23## when R¹ is a carboxylic acyl radical having 1 to 5 carbonatoms and R² is a hydrogen atom.

When R^(a) is a quaternary ammonium salt, it is preferable that both R⁵and R⁶ are hydrogen, or at least one of R⁵ and R⁶ is an alkyl acylradical having 1 to 5 carbon atoms or an alkyl sulfonic acyl radical.

In the compound (1) of the present invention, R^(a) is preferable to bea quaternary ammonium salt. Particularly, it is preferable that R^(d)and R^(e) form together with adjacent nitrogen atom a cyclic alkylaminoradical of 5 to 7 members such as pyrrolidine, piperidine,hexamethyleneimine and the like, or both R^(d) and R^(e) are alkylradicals having 1 to 5 carbon atoms and R^(f) is an alkyl radical having1 to 5 carbon atoms, an alkenyl or alkynyl radical having 2 to 6 carbonatoms. When they have a substituent, it is particularly preferable to behydroxy, carboxy, C₁₋₄ alkoxycarbonyl, halogen, cyano, C₃₋₅ cycloalkyland so on. As X of the quaternary ammonium salt, there are preferablymentioned chlorine, bromine and iodine.

The compound (1) of the present invention can be prepared according tothe following method.

A compound which may be protected, represented by the following formula,is reacted with an acylating, alkylating, boronating, carbonating,sulfinylating or ketalizing agent, followed by the removal ofprotection, if necessary, whereby the compound [1] can be prepared:##STR24## wherein R³ and R^(a) have the same meanings as defined above,A' represents the formula: ##STR25## (wherein Z" represent the formula##STR26## or the formula ##STR27## have the same meanings as definedabove) or the formula: ##STR28##

A compound represented by the following formula or its salt: ##STR29##wherein R¹, R², R³, R⁴ and R^(a) have the same meanings, Z41 'represents the formula ##STR30## (wherein R⁵ and R⁶ have the samemeanings as defined above), the formula ##STR31## (wherein R⁷ has thesame meaning as defined above) or the formula ##STR32## (wherein Y hasthe same meaning as defined above), is treated under a acydic condition,whereby a compound or its salt, represented by the following formula,can be prepared: ##STR33## wherein R¹, R², R³, R⁴, R^(a) and Z'" havethe same meanings as defined above.

The compound [1] can be prepared by subjecting a compound represented bythe following formula to N-alkylation, N-alkenylation or N-alkynylationreaction: ##STR34## wherein A, R¹, R², R³ and R⁴ have the same meaningsas defined above, R^(g) represents --NH--R^(b) (wherein R^(b) has thesame meaning as defined above) or the formula ##STR35## (wherein R^(d)and R^(e) have the same meanings as defined above).

The compound [1] can be prepared by subjecting the compound [2] to aalready known reaction, namely by reacting with an acylating,alkylating, boronating, carbonating, sulfinylating or ketalyzing agent,followed by the removal of protection, if necessary.

The acylating agent employable in the acylation is a reactive derivativeof a carboxylic acid capable of introducing a carboxylic acyl radical,such as an acid halide, an acid anhydride, an amide compound, an activeester or an active thioester. Examples of such reactive derivatives areas follows:

(1) Acid halide

Examples of such acid halides are acid chloride and acid bromide.

(2) Acid anhydride

Examples of such acid anhydrides include mixed anhydrides of monoalkylcarbonic acid, mixed anhydrides of aliphatic carboxylic acids such asacetic acid, pivalic acid, valeric acid, isovaleric acid,trichloroacetic acid etc., mixed anhydrides of aromatic carboxylic acidssuch as benzoic acid, and symmetric acid anhydrides.

(3) Amide compound

A examples of such amide compounds, there can be used compounds whereinan acyl radical is bonded to a nitrogen atom in a ring, such as apyrazole, imidazole, 4-substituted imidazole, dimethylpyrazole orbenzotriazole.

(4) Active ester

Examples of such active esters include methyl ester, ethyl ester,methoxymethyl ester, propargyl ester, 4-nitrophenyl ester,2,4-dinitrophenyl ester, trichlorophenyl ester, pentachlorophenyl ester,mesylphenyl ester, and esters with 1-hydroxy-1H-2-pyridone,N-hydroxysuccinimide or N-hydroxyphthalimide.

(5) Active thioester

Examples of such active thioesters include thioesters with heterocyclicthiols such as 2-pyridylthiol or 2-benzothiazolylthiol.

The above-mentioned reactive derivatives are suitably selected accordingto the kind of the carboxylic acid.

In case a reactive derivative of a polycarboxylic acid is employed asthe acylating agent, carboxyl radicals, except one, are preferablyprotected in the form of esters.

The acylating agent can also be a reactive derivative of a sulfonic acidcapable of introducing a sulfonic acyl radical, for example an acidhalide such as methane sulfonyl chloride, benzylsulfonyl chloride orparatoluene sulfonyl chloride, or a symmetric acid anhydride such asmethane sulfonic anhydride or paratoluene sulfonic anhydride.

In the alkylation, the alkylating agent employable for the alkylation atthe 4"- or 11- position can for example be a corresponding alkyl halide(for example chloride, bromide or iodide), and that employable for thealkylation at the 12- position can for example be dimethyl sulfoxide.

Example of the boronating agents employable in the boronation reactionare alkylboric acids (such as ethylboric acid) and arylboric acids (suchas phenylboric acid).

Examples of the carbonating agents employable in the carbonationreaction are ethylene carbonate, carbonyl diimidazole and thiocarbonyldiimidazole.

Examples of the sulfinylating agents employable in the sulfinylationreaction is ethylene sulfite.

Examples of the ketalyzing agents employable in the ketalyzationreaction are 2-methoxypropene, 2,2-dimethoxypropane,1,1-dimethoxycyclohexane, N,N-dimethylformamide dimethylacetal, andN,N-dimethylacetamide dimethylacetal.

In case of employing a reactive derivative of a carboxylic acid as theacylating agent in the acylation reaction, the amount of said acylatingagent varies according to the number of acyl radicals to be introduced.

The solvent to be employed in the acylation is not limited as long as itdoes not react with the acylating agent, but is preferablydichloromethane, ether, pyridine, chloroform or the like. Examples ofbases are tertiary amines such as triethylamine, diisopropylethylamineand tribenzylamine, and inorganic salts such as potassium carbonate. Thereaction temperature is about 0° C. to 80° C., and the reaction time isabout 10 minutes to 2 weeks.

In case of employing a reactive derivative of a sulfonic acid as theacylating agent in the acylation reaction, the amount of the acylatingagent varies according to the number of acyl radicals to be introduced.

Examples of the solvents to be employed in the acylation are pyridine,chloroform, ether and dichloromethane. Examples of the bases aretertiary amines such as pyridine, tribenzylamine anddiisopropylethylamine. The reaction temperature is about 0° C. to 50°C., and the reaction time is about 10 minutes to 2 days.

The amount of alkylating agent in the alkylation reaction variesaccording to the number of alkyl radicals to be introduced.

Examples of the solvents to be employed in the alkylation reaction arechloroform, dimethyl sulfoxide, dimethyl formamide, ether and ethanol.The reaction temperature is about 0° C. to 80° C., and the reaction timeis about 15 minutes to 1 week. Examples of the base to be employed inthe alkylation at the 4"- or 11- position are tertiary amines such asdiisopropylethylamine or pyridine, sodium hydride and potassium hydride.

In the boronation reaction, the boronating agent is preferably employedin an equivalent amount or in excess (2 -3 times in molar ratio).Examples of the solvents to be employed in the boronation reaction arebenzene, toluene and ether The reaction temperature is about 80° C. to130° C., and the reaction time is about 1 hour to 5 hours.

In the carbonation reaction, the carbonating agent is preferablyemployed in a 2-10 times excess amount, in molar ratio, according to thekind thereof. Examples of the solvent to be employed in the carbonationreaction are benzene and toluene. The reaction temperature is about 25°C. to 130° C., and the reaction time is about 30 minutes to 1 days.

In case of employing ethylene carbonate as the carbonating agent in thecarbonation reaction, the base to be employed can be an inorganic saltsuch as potassium carbonate.

In the sulfinylation reaction, the sulfinylating agent is preferablyemployed in a samll excess (2-3 times in molar ratio). Examples of thesolvents to be employed in the sulfinylation are methanol and ethanol.The reaction temperature is about 20° C. to 30° C., and the reactiontime is about 2 days to 3 days. The base to be employed in saidsulfinylation can be an inorganic salt such as potassium carbonate.

The ketalization reaction should preferably be carried out according tothe ketal exchange reaction by using the compound of the correspondingformula ##STR36##

(wherein R⁹ and R¹⁰ have the same meanings as defined above, Rrepresents a lower alkyl radical such as methyl, ethyl) as theketalyzing agent. As the reaction solvent there can be employedhalogenated hydrocarbons such as chloroform, ethers such astetrahydrofuran, and amides such as dimethylformamide, and it is alsopossible to use the ketalyzing agent itself as the solvent. Although theketalating agent may be used usually in slight excess (about 2 timesmols) to a great excess (about 100 times mols), but the amount ispreferably 2 to 4 times excess in the case of the latter ketalyzingagent. As the catalyst, a strong acid salt of pyridine (such aspyridinium chloride), etc., is preferably used. Particularly in the caseof the present compound, the combination of the latter ketalyzing agentand pyridineum chloride is preferred. The reaction may be conductedpreferably at a temperature of 0° C. to the boiling point of thesolvent, more preferably at around room temperature (about 15° C. to 25°C.). The reaction time may be from several hours to 72 hours, usuallyabout 12 to 24 hours.

In the above-mentioned reactions of the compound [2] which may beprotected, the order of reactivity of hydroxyl radicals on the 2'-, 4"-,11- and 12- positions is 2'>>4"≧11>>12.

In the following there are explained the cases of introducing acarboxylic acyl radical. In case of acylation at the 2'- position only,a chloroform solution of the compound [2] is agitated with an acylatingagent in a small excess (about 2 times in molar ratio) and a base in asmall excess (about 3 times in molar ratio). The reaction is completedin a short time at room temperature, and the desired compound isobtained by purification by silica gel chromatography.

In case of acylation at the 4"- position only, a compound subjected tothe acetylation at the 2'- position as explained above is agitated withan acylating agent and a base in large excess for 15 minutes toovernight at room temperature, then treated in the usual manner andpurified by silica gel chromatography to obtain a2'-0-acetyl-4'-0-acylated compound. The desired compound is obtained byallowing a methanolic solution of the above-mentioned compound to standfor 1 to 2 days at room temperature, and distilling off methanol under areduced pressure, followed by purification by silica gel chromatography.

In case of acylation at the 11- position only, a2'-0-acetyl-4"-formylated compound obtained in the above-explainedmanner is agitated with large excesses of an acylating agent and a basefor several hours to several days at room temperature to about 70° C. toobtain a 2'-0-acetyl-4"-formyl-11- acylated compound, which is thenheated under reflux for about 3 hours to 3 days in methanol to obtainthe desired compound.

In case of acylation at the 12-position only, a 2'-0-acetylated compoundobtained in the above-explained manner is agitated overnight withtrimethylchlorosilane and tribenzylamine and treated in the usual mannerto obtain a 2'-0-acetyl-11, 4"-di-0-silylated compound. A dichloroethanesolution of the compound is agitated with large excesses of an acylatingagent and a base for two days at 75 -80° C. to obtain a 2'-0-acetyl-11,4"-di-0-silyl-12-0-acylated compound, which is treated in the usualmanner and subjected to methanolysis to obtain the desired compound.

In the following, there will explained the case of introducing an alkylradical. In case of alkylation at the 4"-position only, a compound ofwhich the 2'-position is acetylated in the above-explained manner isdissolved in dichloromethane, added with an alkylating agent and a baseunder cooling with ice, and is let to stand for 30 minutes at roomtemperature to obtain a 2'-0-acetyl-4"-0-alkylated compound. Thiscompound is dissolved in methanol, then is let to stand for one day atroom temperature, and the reaction solution is concentrated under areduced pressure and is purified by silica gel chromatography to obtainthe desired compound.

In case of alkylation at the 11-position only, the compound [2] isreacted with excessive amounts of benzyloxycarbonyl chloride and sodiumhydrogen carbonate, and the 3'-dimethylamino radical are protected by,in the latter case, by methyl radical of it by the acyl. It is thendissolved in dimethyl formamide and reacted with an alkylating agent anda base under cooling with ice. The product is then dissolved in waterand ethanol, then subjected to hydrogenolysis in the presence of apalladium-carbon catalyst, and hydrogenated in the presence offormaldehyde to obtain the desired compound.

In case of alkylation at the 12-position only, a compound, of which the2'-, 4"- and 11- position are acetylated in the above-explained manner,is dissolved in dimethyl sulfoxide and is let to stand, with a largeexcess of acetic anhydride, for 96 hours to 1 week at room temperature.The reaction solution is then concentrated under a reduced pressure, andpurified by silica gel chromatography, and the obtained compound isdissolved in methanol and heated with lithium hydroxide at 50° C. for 4hours to obtain the desired compound.

Preferred examples of the protecting radicals are acetyl for the 2'-position, formyl and silyl for the 4'-position, and acetyl and silyl forthe 11- position.

A compound [2] having a protective radicals can be prepared in processessimilar to that explained above.

If thus prepared compound [1] has a protective radicals, they may beremoved if necessary. The removal of the protective radical can besuitably achieved in the usual manner, for example, by a method using abase (alkaline hydrolysis), a method using hydrazine or a reductionmethod, according to the kind of the protective radicals. In the methodusing a base, there can be employed, depending on the kind of theprotective radicals and other conditions, for example, a hydroxide of analkaline metal such as sodium, potassium or lithium or an alkali earthmetal such as calcium or magnesium, an inorganic base such as acarbonate, a metal alkoxide, an organic amine, an organic base such asquaternary ammonium salt, or a basic ion exchange resin. If the methodusing a base is conducted in the presence of a solvent, said solvent isusually a hydrophilic organic solvent, water or a mixture thereof.

The reduction method is conducted, for example, in the presence of areducing metal catalyst, depending on the kind of protective radicalsand other conditions, and the examples of such catalyst employable incatalytic reduction include platinum catalysts such as platinum sponge,platinum asbestos, platinum black, platinum oxide and colloidalplatinum: palladium catalysts such as palladium sponge, palladium black,palladium oxide, palladium on barium sulfate, palladium on bariumcarbonate, palladium on activated carbon, colloidal palladium andpalladium on silica gel; reduced nickel, nickel oxide, Raney nickel andUrushibara nickel. The reduction method is usually conducted in asolvent, which is usually composed of an alcohol such as methanol,ethanol, propyl alcohol or isopropyl alcohol, or ethyl acetate.

The method using a base or the reduction method is usually conductedunder cooling or under heating.

In the reaction in which the compound [3] is treated under acidicconditions to prepare the compound [4], there can be employed, foracidification, an organic acid such as acetic acid, pyridinium chlorideor pyridinium paratoluene sulfonate.

The reaction temperature is about 0° C. to 30° C., the reaction time isabout 30 minutes to 1 hour, and the range of pH in reaction is 1 to 6.The solvent employable in the reaction is, for example, acetic acid,chloroform, dichloromethane or ether, and the reaction is preferablyconducted under agitation.

By subjecting a compound [5'] which corresponds to the compound [5] inwhich R⁹ is a formula --NH--R^(b) (wherein R^(b) is the same meaning asdefined above) to N-alkylation, N-alkenylation or N-alkynylation, acompound [1'] which corresponds to the compound [1] in which R^(a) isthe formula ##STR37##

(wherein R^(b) and R^(c) have the same meanings as defined above) can beprepared.

The reaction is carried out by reacting a corresponding ketone oraldehyde to the compound [5'] under the reduction conditions. As thereduction conditions, catalytic reduction can be used [see R. K. ClarkJr. and M. Flyfelder, ANTIBIOTICS AND CHEMOTHERAPY, 7, 483 (1957)]. Thecatalyst usable therefor may be those as described in the previous itemof reductive deprotection, particularly preferable being palladiumblack, palladium carbon, and Raney nickel. The reaction can bepreferably carried out in alcohols (such as methanol and ethanol),ethers (such as tetrahydrofuran and dimethoxyethane) and aqueousmixtures thereof, in the presence of hydrogen gas, under ice cooling toabout 80°, preferably around room temperature.

As the reduction condition, reduction by use of a metal hydride may alsobe used. As the metal hydride sodium borohydride, sodiumcyanoborohydride are preferred.

The reaction is carried out preferably in a solvent such as alcohols(e.g. methanol and ethanol), ethers (e.g. tetrahydrofuran anddimethoxyethane), nitriles (e.g. acetonitrile) and aqueous mixturesthereof, more preferably while maintaining the pH of the reactionmixture at neutral to weakly acidic (pH about 3 to 6), and it ispreferable for control of the pH, to add a buffer solution or mineralacid (such as hydrochloric acid), an organic acid (such as acetic acid)or an aqueous solution thereof.

The amount of the metal hydride used is varied, depending on thecarbonyl compound used, but it is a slight excess over to about 100times the theoretical amount, preferably a slight excess to about 10times thereof, and it is added suitably with the progress of thereaction.

The reaction is carried out at about -20° C. to 80° C., preferably atabout 0° C. to 30° C..

The compound [1'] can also be synthesized by allowing the compound [5']to react with, for example, corresponding alkyl, alkenyl or alkynylhalide, an ester, trioxonium salt, etc., in the presence of a base.

Examples of the bases include sodium hydroxide, potassium hydroxide,sodium hydrogen carbonate, potassium carbonate, butyl lithium phenyllithium and sodium hydride.

Examples of the halogen atoms in the halide include chlorine, bromineand iodine, particularly preferably iodine.

Examples of the esters include a sulfate ester and the like.

Typical examples of the trioxonium salts include trimethyloxoniumfluoroborate, triethyloxonium fluoroborate, etc.

The reaction reagents are each about 1 to 100 mol equivalent, preferablyabout 2 to 25 mol equivalent per 1 mol of the starting compound.

Examples of the solvents to be used in the reaction include preferablyhalogenated hydrocarbons (such as chloroform and dichloromethane),ethers (such as ethyl ether and tetrahydrofuran), esters (such as ethylacetate), alcohols (such as methanol and ethanol), etc.

The reaction is carried out under ice cooling (about 0° C.) to theboiling point of the solvent (to about 100° C.), preferably at roomtemperature (about 15° to 25° C.) to about 80° C.

The reaction time is about 2 to 48 hours.

By subjecting the above compound [1'] to N-alkylation, N-alkenylation orN-alkynylation reaction (quarternary ammoniating reaction), a compound[1"] which corresponds to a compound [1] in which R^(a) is the formula##STR38##

(wherein R^(d), R^(e), R^(f) and X⁻ have the same meanings as definedabove) can be prepared.

Examples of the reagents to be used in the reaction includecorresponding alkyl, alkenyl or alkynyl halides, esters, trioxoniumsalts, etc.

Examples of the halogen atoms in the halides include chlorine, bromineand iodine, particularly preferably iodine.

Examples of the esters include a sulfate ester and the likes.

Typical examples of the trioxonium salts include trimethyyloxoniumfluoroborate, triethyloxonium fluorobrate, etc.

The reaction reagent is used in an amount of about 1 to 100 molequivalent, preferably about 2 to 25 mol equivalent per one mol of thestarting compound.

The solvent to be used in the reaction include, for example, haloganatedhydrocarbons (such as chloroform and dichloromethane), ethers (such asethyl ether and tetrahydrofuran), esters (such as ethyl acetate),alcohols (such as methanol and ethanol), etc.

The reaction is carried out under ice cooling (about 0° C.) to theboiling point of the solvent (about 100° C.), preferably at roomtemperature (about 15° to 25° C.) to about 80° C.

The reaction time is about 2 to 48 hours.

The quaternization can be conducted before or after the foregoingacylation reaction and the like, preferably thereafter.

From the reaction mixture, after carrying out optionally washing withaqueous sodium carbonate, or aqueous sodium chloride, drying orconcentration, the product can be isolated by filtration of theprecipitate formed by addition of an ether to obtain the desiredproducts as a salt of the anion from the reagent used in quaternization.

When the reaction mixture is subjected to column chromatography withsilica gel or ion exchange resin, using, for example, a mixture ofchloroform-metanol added with conc. aqueous ammonia, a compound withhydroxide ion (OH⁻) as the anion can be obtained.

The anions of the compound thus obtained can be exchanged with otheranions by a conventional means.

The starting compound [5'] can be prepared by treating, for example,de(N-methyl)erythromycin A or bis [de(N-methyl)] erythromycin A [E. H.Flynn, et al., Journal of the American Chemical Society, 77, 3104(1955), Japanese Laid-open Patent Application No. 9129/1972] underacidic conditions.

The compound [1] thus obtained can be isolated and purified in per sealready known methods, for example concentration, pH alteration,solvent-transformation, solvent extraction, lyophilization,crystallization, recrystallization, distillation, chromatography etc.

The compound [1] may form a salt with an acid. Examples of such acidsinclude organic acids (for example, ethylsuccinic acid, glycopeptonicacid, stearic acid, propionic acid, succinic acid, lactic acid,trifluoroacetic acid, acetic acid, methanesulfonic acid,paratoluenesulfonic acid, and benzenesulfonic acid) and mineral acids(for example, sulfuric acid, hydrochloric acid, hydriodic acid,phosphoric acid, nitric acid).

The raw material for preparing the compound [1] can be prepared, forexample, by methods reported by W. Slawinski et al., Journal of theRoyal Netherlands Chemical Society, 94 236, 1975; V. C. Stephens et at.,Antibiotics Annual, 1958-1959, 346; P. H. Jones et al., Journal ofMedicinal Chemistry, 15, 631, 1972; J. Tadanier et al., Journal ofOrganic Chemistry, 39, 2495, 1974; A. Banaszek et al., Roczniki Chemi,43, 763, 1969; C. W. Pettinga et al., Journal of the American ChemicalSodiety, 76, 569, 1954; P. F. Wiley et al., Journal of the AmericanChemical Society, 79, 6074, 1957; J. Majer et al., Journal of theAmerican Chemical Society, 99, 1620, 1977; and J. R. Martin et al.,Journal of Antibiotics, 35, 426, 1982 or similar methods, or bysubjecting the compounds described in the above-mentioned references tothe above-described process or the conventional known means.

On the other hand, the starting compounds anhydroerythromycin A can beprepared according to the methods reported by P. Kurath, et al.,Experientia, 27, 362 (1971), K. Krowichki and A. Zamojski, The Journalof Antibiotics, 26, 569 (1973), while 9-dihydroerythromycin A6,9-epoxide and 9-dihydroerythromycin B 6,9-epoxide can be preparedaccording to the methods reported in Japanese Laid-open PatentApplication No. 1588/1974.

The compound [1] or its salt has an excellent effect on stimulating thegastrointestinal contraction. Also, no lethal case was observed when thecompound (55) described later is orally administered to mouse at a doseof 2300 mg/kg. Accordingly, the compound [1] be considered to be low intoxicity.

The compound [1] shows an excellent effect for stimulating thegastrointestinal contraction with a low toxicity, and the preparation ofthe present invention containing the compound [1] can therefore beutilized as a gastrointestinal contractive motion stimulant for thetherapy of digestive malfunctions (nausea, vomiting, want of apetite ingastritis, gastric ulcer, duodenal ulcer, diseases in gallbladder andbiliary tract, etc.) in mammals (mouse, rat, dog, cow, pig, man, etc.).

The digestive tract contractive motion stimulant of the presentinvention can be administered orally or non-orally to theabove-mentioned mammals. The daily dose thereof, in case of oraladministration, is ca. 0.0001-100 mg/kg in the form of the compound [1],and, in case of non-oral administration, for example, intravenousinjection, is ca. 0.00001-10 mg/kg.

For example, a compound (32), to be explained later, induces anextremely strong contraction in the stomach, duodenum and smallintestine in dog, by an intravenous administration of a dose of 1.0mg/kg. The contractile motion is comparable to the strongest one in thegastrointestinal contraction in normal dog. Also a reduced dose in theorder of 3 μg/kg induces, instead continuous strong contraction, acontractile motion of an identical pattern with that of the naturalcontraction inter digestive state.

The digestive tract contractile motion stimulant of the presentinvention can be formed into various preparations, containing thecompound [1] and additional components, such as emulsion, hydratedmixture, tablet, solution, powder, granules, capsule, pill etc. Saidadditional components include pharmacologically permitted vehicle,disintegrator, lubricant, binder, dispersant, plasticizer etc. Asexamples of the additional components, the examples of vehicles arelcactose, glucose and white sugar; those of disintegrators are starch,sodium alginate, agar powder and carboxymethyl cellulose calcium; thoseof lubricants are magnesium stearate, talc and liquid paraffin; those ofbinders are syrup, gelatin solution, ethanol and polyvinyl alcohol;those of dispersants are methyl cellulose, ethyl cellulose and shellac;and those of plasticizers are glycerin and starch.

These preparations can be obtained by methods usually employed in thefield of pharmaceuticals.

The present invention will now be clarified in further detail byreference examples and examples, but the present invention is notlimited thereby.

PREFERRED EMBODIMENTS OF THE INVENTION

The gastrointestinal motion was measured in the following manner (Z.Itoh, Nihon Heikatsu-kin Gakkai Zasshi, 13, 33, 1976). A crossbreedadult dog of a weight of 10-15 kg was anesthethized and the abdominalcavity was opened, and force transducers were chronically sutured on theserosa of the gastrointestinal tract such as gastric body, gastricantrum, duodenum, jejunum, etc. in directions capable of recording thecontraction of circular muscles. The lead wires were extracted from theback and fixed to the skin. The experiment could be started about 5 daysafter recovery from such operation, and a dog prepared in this mannercan be subjected to experiments for about 6 months. The forcetransducer, when subjected to a bending stress by the contraction of thegastrointestinal tract where the transducer is sutured, allows to recordthe wave form corresponding to the applied force, on a pen-recordingoscillograph, and this method allows to measure the nature and magnitudeof the contraction.

The dog was maintained in an experimental cage, and the wave form ofcontraction can be immediately recorded by connecting the wires of thetransducer to the polygraph. The gastrointestinal contractive motion canbe divided, from the pattern of contraction, into the one in a periodafter food intake and it in an interdigestive period. The experimentswere conducted, during the interdigestive period and in an inactiveperiod lacking the contraction in the stomach. The sample was injectedthrough a silicone tube placed in advance in the superior vena cava over10 seconds.

The sample was dissolved in physiological saline to a total volume of 10ml. and was slowly injected intravenously for a period of ca. 10seconds.

The gastrointestinal motor stimulating activity (GMSA) is summarized inTable 1.

                                      TABLE 1    __________________________________________________________________________     ##STR39##    Compound    No.*  R.sup.1  R.sup.2                         R.sup.5  R.sup.6                                         R.sup.a       GMSA    __________________________________________________________________________    (5)   H        CH.sub.3 CO                         H        H                                          ##STR40##     +    (9)   H        CHO   H        H      "              ++    (14)  H        CH.sub.3 CO                         CH.sub.3 CO                                  H      "              +    (25)  H        CHO   CH.sub.3 SO.sub.2                                  H      "              +++    (26)  H        CH.sub.3 SO.sub.2                         CH.sub.3 SO.sub.2                                  H      "              ++    (28)  CH.sub.3 CH.sub.2 CH.sub.2 CO                   H     H        H      "              ++    (30)  H        CH.sub.3 SO.sub.2                         H        H      "              +    (32)  H        H     CH.sub.3 CO                                  CH.sub.3 CO                                         "              +++    (33)  H        H     CH.sub.3 CH.sub.2 CO                                  CH.sub.3 CH.sub.2 CO                                         "              ++    (36)  H        H                          ##STR41##                                          ##STR42##    +    (37)  H        H                          ##STR43##      "             +    (39)  H        H                          ##STR44##      "             ++    (47)  H        H     H        CH.sub.3 SCH.sub.2                                         "             +    (50)  H        H     CH.sub.3 CO                                  H      "             ++    (51)  H        H     CH.sub.3 CH.sub.2 CO                                  H      "             ++    (52)  H        H     CH.sub.3 CH.sub.2 CH.sub.2 CO                                  H      "             ++    (54)  H        H                          ##STR45##      "             +    (55)  H        H     H        H                                          ##STR46##    +++    (56)  H        H     CH.sub.3 CO                                  CH.sub.3 CO                                         "             +++    (58)  H        H     CH.sub.3 SO.sub.2                                  H      "             +++    (59)  H        CHO   CH.sub.3 SO.sub.2                                  H      "             +++    (60)  H        H     H        H                                          ##STR47##    ++ +    (62)  CH.sub.3 CO                   H     H        H                                          ##STR48##    ++    (73)  H        H     CH.sub.3 (CH.sub.2).sub.3 CO                                  H                                          ##STR49##    +    (74)  H        H     CH.sub.3 (CH.sub.2).sub.4 CO                                  H      "             ++    (75)  H        H     H        H                                          ##STR50##    +++    (77)  H        H     H        H                                          ##STR51##    +++    (79)  H        H     H        H                                          ##STR52##    +++    (80)  H        H     H        H                                          ##STR53##    +    (81)  H        H     H        H                                          ##STR54##    +++    (82)  H        H     H        H                                          ##STR55##    +++    (83)  H        H     H        H                                          ##STR56##    +++    (89)  H        H     H        H                                          ##STR57##    +++    (90)  H        H     SO.sub.2 CH.sub.3                                  H                                          ##STR58##    +++    (91)  H        H     SO.sub.2 CH.sub.3                                  H                                          ##STR59##    +++    (92) (60-4)          H        H     H        H                                          ##STR60##    +++    (97)  H        H     H        H                                          ##STR61##    ++    (98)  H        H     H        H                                          ##STR62##    +++    (99)  H        H     H        H                                          ##STR63##    +    (100) H        H     H        H                                          ##STR64##    ++    (101) H        H     H        H                                          ##STR65##    +    (102) H        H     H        H                                          ##STR66##    +++    (103) H        H     H        H                                          ##STR67##    +    (104) H        H     H        H                                          ##STR68##    ++++    (105) H        H     COCH.sub.3                                  COCH.sub.3                                          ##STR69##    +++    (106) H        H     CH.sub.3 H      N(CH.sub.3).sub.2                                                       ++    (108) H        H     COC.sub.2 H.sub.5                                  COCH.sub.3                                         N(CH.sub.3).sub.2                                                       ++    (109) H        H     COC.sub.3 H.sub.7                                  COCH.sub.3                                         N(CH.sub.3).sub.2                                                       ++    (110) H        H     COCH.sub.3                                  COCH.sub.3                                          ##STR70##    +++    (111) H        H     H        H                                          ##STR71##    ++    (112) H        H     H        H                                          ##STR72##    ++    (113) H        H     H        H                                          ##STR73##    +++    (114) H        H     H        H                                          ##STR74##    +++    (117) H        H     H        H                                          ##STR75##    ++    (119) H        H     H        H                                          ##STR76##    +++    (124) H        H     H        H                                          ##STR77##    ++    (128) H        H     H        H                                          ##STR78##    ++    (129) H        H     H        H                                          ##STR79##    +++    (130) H        H     H        H                                          ##STR80##    +++    (140) H        H     H        H                                          ##STR81##    ++++    __________________________________________________________________________

                  TABLE 1'    ______________________________________     ##STR82##    Compound    No.         R             X.sup.⊖                                     GMSA    ______________________________________    (85)        CH.sub.3      I.sup.⊖                                     +++    (86)        C.sub.2 H.sub.5                              I.sup.⊖                                     +++    (87)        (CH.sub.2).sub.2 CH.sub.3                              I.sup.⊖                                     ++    (88)        (CH.sub.2).sub. 3 CH.sub.3                              I.sup.⊖                                     +++    (115)       CH.sub.2 CHCH.sub.2                              Br.sup.⊖                                     +++    (116)       CH.sub.2 CCH  Br.sup.⊖                                     +++    ______________________________________

                  TABLE 1"    ______________________________________     ##STR83##    Compound No.   Z             GMSA    ______________________________________    *4                    ##STR84##    ++    *5                    ##STR85##    +    *6                    ##STR86##    +    ______________________________________

In Tables 1, 1' and 1", ++++, +++, ++ and + of GMSA respectivelyindicate that the minimum effective concentration required for inducinga gastrointestinal contractive motion in dog, comparable to thespontaneous one in the interdigestive period is in a range of 0.01-0.1μg/kg, 0.1-10 μg/kg, 10-30 μg/kg and 30-50 μg/kg, respectively,

(*1) The numbers of compounds correspond to those in the referenceexamples.

The process for preparing the compounds represented by *2, *5 and *6 isdescribed in a reference, J. Tadanier et al., Journal of OrganicChemistry 39, 2495, 1974.

The process for preparing the compounds represented by *3 is describedin a reference, W. Slawinski et al., Journal of the Royal NetherlandsChemical Society 94, 236, 1975.

The process for preparing the compounds represented by *4 is describedin a reference, P. Kurath, et al., Experientia, 27, 362, 1971.

REFERENCE EXAMPLE 1

250 mg of 2'-0-acetyl-8,9-anhydroerythromycin A 6,9-hemiketal(compound 1) (V. C Stephens et al., Antibiotics Annual, 1958-1959, 346)was dissolved in 2 ml of dry pyridine, and 0.3 ml of acetyl chloride wasadded at a time at room temperature and under vigorous agitation. Afteragitation for 15 minutes, 30 ml of ethyl acetate was added. The obtainedethyl acetate solution was washed with the saturated agueous solution ofsodium hydrogen carbonate, then with the saturated agueous solution ofsodium chloride, then dried with anhydrous sodium sulfate, and thesolvent was distilled off to obtain a crude product.

The crude product was purified by silica gel column chromatography(developed with a 50:1:0.01 mixed solvent of chloroform, methanol andconcentrated agueous ammonia) to obtain 100 mg (yield 38%) of2',4"-di-0-acetyl-8,9-anhydroerythromycin A 6,9-hemiketal (compound 2)as white powder.

REFERENCE EXAMPLE 2

303 mg of the compound 1, 0.3 ml of propionyl chloride and 2 ml of drypyridine were employed in the process of Example 1 to obtain 143 mg(yield 44%) of 2'-0-acetyl-4"-0-propionyl-8,9-anhydroerythromycin A6,9-hemiketal (compound 3) as white powder.

REFERENCE EXAMPLE 3

303 mg of the compound 1 was dissolved in 1 ml of dry pyridine andagitated overnight with 0.07 ml of benzoyl chloride. Thereafter the sameprocess as in Reference Example 1 was adopted to obtain 127 mg (yield37%) of 2'-0-acetyl-4"-0-benzoyl-8,9-anhydroerythromycin A 6,9-hemiketal(compound 4) in white powder.

REFERENCE EXAMPLE 4

100 mg of the compound 2 obtained in Reference Example 1 was dissolvedin 2 ml of methanol, and agitated overnight at room temperature. A crudeproduct, obtained by distilling off the solvent, was purified by silicagel column chromatography (developed by a 50:1:0.01 mixture ofchloroform, methanol and concentrated aqueous ammonia) to obtain 35 mg.(yield 37%) of 4"-0-acetyl-8,9-anhydroerythromycin A 6,9-hemiketal(compound 5) in white powder.

REFERENCE EXAMPLE 5

143 mg of the compound 3 obtained in Reference Example 2 was dissolvedin 2 ml of methanol, and processed in the same manner as in ReferenceExample 4 to obtain 83 mg (yield 61%) of4"-0-propionyl-8,9-anhydroerythromycin A 6,9-hemiketal (compound 6)inwhite powder.

REFERENCE EXAMPLE 6

127 mg of the compound 4 obtained in Reference Example 3 was dissolvedin 2 ml of methanol, and was processed in the same manner as inReference Example 4 to obtain 92 mg (yield 77%) of4"-0-benzoyl-8,9-anhydroerythromycin A 6,9-hemiketal (compound 7) inwhite powder.

REFERENCE EXAMPLE 7

59 mg of 2'-0-acetyl-4"-0-formyl-8,9-anhydroerythromycin A 6,9-hemiketal(compound 8) (J. Tadanier et al., Journal of Organic Chemistry, 39,2495, 1974) was dissolved in 1 ml of methanol, and was processed in thesame manner as in Reference Example 4 to obtain 29 mg of4"-0-formyl-8,9-anhydroerythromycin A 6,9-hemiketal (compound 9) inwhite powder.

REFERENCE EXAMPLE 8

303 mg of the compound 1 was dissolved in 2 ml of dry pyridine, amd 0.3ml of crotonyl chloride was added at a time under vigorous agitation atroom temperature. After agitation for 15 minutes, 30 ml of ethyl acetatewas added. The obtained ethyl acetate solution was washed with thesaturated aqueous solution of sodium hydrogen carbonate and with thesaturated aqueous solution of sodium chloride, then dried with anhydroussodium sulfate and the solvent was distilled off.

The obtained residue was dissolved in 2 ml of methanol, and agitatedovernight at room temperature. A crude product obtained by removing thesolvent by distillation was purified by silica gel column chromatography(developed with a 50:1:0.01 mixture of chloroform, methanol andconcentrated aqueous ammonia) to ob tain 31 mg (yield 10%) of4"-0-crotonyl-8,9-anhydroerythromycin A, 6,9-hemiketal (compound 10) inwhite powder.

REFERENCE EXAMPLE 9

205 mg of the compound 1, 2 ml of dry 0.3 ml of butyryl chloride wereprocessed in the same manner as in Reference Example 8 to obtain 18 mg(yield 8%) of 4"-0-butyryl-8,9-anhydroerythromycin A 6,9-hemiketal(compound 11) in white powder.

REFERENCE EXAMPLE 10

303 mg of the compound 1, 2 ml of dry pyridine and 0.4 ml of isovalerylchloride were processed in the same manner as in Reference Example 8 toobtain 40 mg (yield 12%) of 4"-0-isovaleryl-8,9-anhydroerythromycin A6,9-hemiketal (compound 12) in white powder.

REFERENCE EXAMPLE 11

303 mg of the compound 1, 2 ml of dry pyridine, and 0.4 ml. ofethylmalonyl chloride were processed in the same manner as in ReferenceExample 8 to obtain 40 mg (yield 12%) of4"-0-ethylmalonyl-8,9-anhydroerythromycin A 6,9-hemiketal (compound 13)in white powder.

REFERENCE EXAMPLE 12

205 mg of the compound 1 was dissolved in 1 ml of dry pyridine, andagitated for 4 days at room temperature with 0.25 ml of aceticanhydride. The mixture was diluted with 30 ml of ethyl acetate, thenwashed with the saturated aqueous solution of sodium hydrogen carbonateand the saturated aqueous solution of sodium chloride, and dried withanhydrous sodium sulfate. The residue, obtained by distilling off thesolvent, was dissolved in 1 ml of methanol and agitated overnight atroom temperature. A crude product, obtained by removing the solvent bydistillation, was purified with silica gel column chromatography(developed with a 50 : 1 : 0.01 mixture of chloroform, methanol andconcentrated aqueous ammonia water to obtain 129 mg (yield 60%) of11,4"-di-0-acetyl-8,9-anhydroerythromycin A 6,9-hemiketal (compound 14)in white powder.

REFERENCE EXAMPLE 13

205 mg of the compound 1, 1 ml of dry pyridine and 0.25 ml of propionicanhydride were processed in the same manner as in Reference Example 12to obtaine 105 mg (yield 47%) of11,4"-di-0-propionyl-8,9-anhydroerythromycin A 6,9-hemiketal (compound15) in white powder.

REFERENCE EXAMPLE 14

205 mg of the compound 1 was dissolved in 1 ml of dry pyridine, andagitated with 0.5 ml of butyric anhydride for 7 days at roomtemperature. It was thereafter processed in the same manner as ReferenceExample 12 to obtain 113 mg (yield 40%) of11,4"-di-0-butyryl-8,9-anhydroerythromycin A 6,9-hemiketal (compound 16)in white powder.

REFERENCE EXAMPLE 15

205 mg of the compound 1 was dissolved in 1 ml of dry pyridine, andagitated with 0.5 ml of benzoyl chloride for 3 days at room temperature.The mixture was then processed in the same manner as in Example 12 toobtain 107 mg (yield 35%) of 11,4"-di-0-benzoylerythromycin A6,9-hemiketal (compound 17) in white powder.

REFERENCE EXAMPLE 16

184 mg of the compound 1 was dissolved in 2 ml of dry pyridine, andagitated with 440 mg of benzylsulfonyl chloride for 5 hours at roomtemperature. The mixture was then diluted with 30 ml of ethyl acetate,washed with the saturated aqueous solution of sodium hydrogen carbonateand with the saturated aqueous solution of sodium chloride, and driedwith anhydrous sodium sulfate. The residue obtained by removing thesolvent by distillation was dissolved in 2 ml of methanol, and agitatedovernight at room temperature. A crude product obtained by removing thesolvent by distillation wa purified by silica gel column chromatography(developed by a 50:1:0.01 mixture of chloroform, methanol andconcentrated aqueous ammonia) to obtain 127 mg (yield 51%) of11,4"-di-0-benzylsulfonyl-8,9-anhydroerythromycin A 6,9-hemiketal(compound 18) in white powder.

REFERENCE EXAMPLE 17

227 mg of the compound 1 was dissolved in 2 ml of dry pyridine, andagitated with 527 mg of paratoluenesulfonyl chloride for 2 days at 50°C. The mixture was processed in the same manner as in Reference Example16 to obtain 81 mg (yield 26%) of11,4"-di-0-paratoluenesulfonyl-8,9-anhydroerythromycin A 6,9-hemiketal(comp 19) in white powder.

REFERENCE EXAMPLE 18

9 g of 8,9-anhydroerythromycin A 6,9-hemiketal cyclic-11,12 carbonate(compound 20) (W. Slawinski et al., Journal of the Royal NetherlandsChemical Society, 94, 236, 1975) was dissolved in 100 ml of chloroformand agitated with 4 ml of pyridine and 3 ml of acetic anhydride for 45minutes at room temperature. This reaction solution was washed with thesaturated aqueous solution of sodium hydrogen carbonate and with thesaturated aqueous solution of sodium chloride, then dried with anhydroussodium sulfate, and the solven was distilled off to obtain white powderof 2'-0-acetyl-8,9-anhydroerythromycin A 6,9-hemiketalcyclic-11,12-carbonate (compound 21) quantatively in substatially purestate.

REFERENCE EXAMPLE 19

235 mg of the compound 21 obtained in Example 18 was dissolved in 1 mlof dry pyridine, and agitated with 0.5 ml butyric anhydride for 2 daysat room temperature. The reaction solution was diluted with 30 ml ofethyl acetate, then washed with the saturated aqueous solution of sodiumhydrogen carbonate and with the saturated aqueous solution of sodiumchloride, dried with anhydrous sodium sulfate and the solvent wasdistilled off to obtain a crude product.

The crude product was purified by silica gel column chromatography(developed by a 50:1:-0.01 mixture of chloroform, methanol andconcentrated aqueous ammonia) to obtain 78 mg (yield 31%) of2'-0-acetyl-4"-0-butyryl-8,9-anhydroerythromycin A6,9-hemiketal-cyclic-11,12-carbonate (compound 22) in white powder.

REFERENCE EXAMPLE 20

59 mg of the compound 22 obtained in Reference Example 19 was dissolvedin 1 ml of methanol, and agitated overnight at room temperature. A crudeproduct obtained by removing the solvent by distillation was purified bysilica gel column chromatography (developed by a 50:1:0.01 mixture ofchloroform, methanol and concentrated aqueous ammonia) to obtain 40 mg(yhield 72%) of 4"-0-butyryl-8,9-anhydroerythromycin A6,9-hemiketal-cyclic-11,12-carbonate (compound 23) in white powder.

REFERENCE EXAMPLE 21

79 mg of11-0-methanesulfonyl-2'-0-acetyl-4"-0-formyl-8,9-anhydroeryth-romycin A6,9-hemiketal (compound 24) (J. Tadaniel et al., Journal of OrganicChemistry, 39, 2495, 1974) was dissolved in 1 ml of methanol, andagitated overnight at room temperature. A crude product obtained byremoving the solvent by distillation was purified by silica gel columnchromatography (developed by a 50:1:0.01 mixture of chloroform, methanoland concentrated aqueous ammonia) to obtain 40 mg (yield 52%) of11-0-methanesulfonyl-4"-0-formyl-8,9-anhydroerythromycin A 6,9-hemiketal(compound 25) in white powder.

REFERENCE EXAMPLE 22

150 mg of the compound 1 was dissolved in 2 ml of dry pyridine, and 46μl of methanesulfonyl chloride was added thereto under agitation andunder cooling with ice. After completion of the addition, agitation wascontinued for 1 hour under cooling with ice, and then for 2 hours atroom temperature. The same process as in Example 16 was thereafterconducted to obtain 123 mg (yield 78%) of11,4"-di-0-methanesulfonyl-8,9-anhydroerythromycin A 6,9-hemiketal(compound 26) in which powder.

Low mass (SIMS) m/e/ : 872 (M+H)⁺

The structure, specific rotatory power and NMR spectrum values of thecompounds obtained in Reference Example 1 to 22 are summarized in Tables2 and 3.

                                      TABLE 2    __________________________________________________________________________     ##STR87##    Compound    No.   R.sup.1               R.sup.2     R.sup.5     R.sup.6                                         [α].sub.D.sup.24                                         ( -c1.0,CHCl.sub.3)    __________________________________________________________________________     2    CH.sub.3 CO               CH.sub.3 CO H           H -44.4°     3    CH.sub. 3 CO               CH.sub.3 CH.sub.2 CO                           H           H -46.0° ( -c 0.5)     4    CH.sub.3 CO               PhCO        H           H -56.2°     5    H    CH.sub.3 CO H           H -43.4°     6    H    CH.sub.3 CH.sub.2 CO                           H           H -38.0°     7    H    PhCO        H           H -59.2°     9    H    CHO         H           H -41.8°    10    H                ##STR88##  H           H -43.4°    11    H    CH.sub.3 CH.sub.2 CH.sub.2 CO                           H           H -33.4°    12    H                ##STR89##  H           H -35.0°    13    H                ##STR90##  H           H -34.8°    14    H    CH.sub.3 CO CH.sub.3 CO H -21.4°    15    H    CH.sub.3 CH.sub.2 CO                           CH.sub.3 CH.sub.2 CO                                       H -25.6°    16    H    CH.sub.3 CH.sub.2 CH.sub.2 CO                           CH.sub.3 CH.sub.2 CH.sub.2 CO                                       H -25.4°    17    H    PhCO        PhCO        H -50.0°    18    H    PhCH.sub.2 SO.sub.2                           PhCH.sub.2 SO.sub.2                                       H -37.6°    19    H                ##STR91##                            ##STR92##  H -9.0°    21    CH.sub.3 CO               H                            ##STR93##    -33.6°    22    CH.sub.3 CO               CH.sub.3 CH.sub.2 CH.sub.2 CO                            ##STR94##    -41.2°    23    H    CH.sub.3 CH.sub.2 CH.sub.2 CO                            ##STR95##    -42.6°    25    H    CHO         CH.sub.3 SO.sub.2                                       H -32.4°    26    H    CH.sub.3 SO.sub.2                           CH.sub.3 SO.sub.2                                       H -34.8°    __________________________________________________________________________     In Table 2, Ph is phenyl and Et is ethyl.     The numbers of compounds correspond to those in the Reference Examples.

                                      TABLE 3    __________________________________________________________________________    .sup.3 H-NMR peak (δ value ppm, solvent CDCl.sub.3)    Compound No.            3"-OMe(s,3H)                    3'-NMe.sub.2 (s,6H)                            8-Me(s,3H)                                  Others    __________________________________________________________________________    2       3.35    2.28    1.55  2'-OAc: 2.05 (s,3H), 4"-OAc 2.10 (s,3H)    3       3.35    2.28    1.55  Ac: 2.04 (s,3H)    4       3.34    2.33    1.55  Ac: 2.06 (s,3H) Ph: 7.45(m,3H) 8.00(m,2H)    5       3.33    2.31    1.57  Ac: 2.10 (s,3H)    6       3.32    2.32    1.57    7       3.40    2.35    1.56  Ph: 7.49 (m,3H) 8.01(m,2H)    9       3.33    2.30    1.56  CHO: 8.19(s,1H)    10      3.33    2.31    1.56                                   ##STR96##    11      3.32    2.29    1.55    12      3.33    2.31    1.57    13      3.32    2.30    1.57                                   ##STR97##    14      3.32    2.30    1.57  4"-OAc: 2.09(s,3H),11-OAc: 2.12 (s,3H)    15      3.31    2.28    1.57    16      3.32    2.35    1.57    17      3.41    2.35    1.56  Ph: 7.49 (m,6H) 8.03(m,4H)    18      3.33    2.28    1.53  SO.sub.2 .sub.----CH.sub.2Ph: 4.34 & 4.52                                  respectively (S,2H), Ph: 7.40(S, 10H)    19      3.30    2.29    1.52                                   ##STR98##    21      3.46    2.36    1.58  Ac: 2.05 (s,3H)    22      3.34    2.28    1.58  Ac: 2.05 (s,3H)    23      3.28    2.26    1.57    25      3.34    2.33    1.58  SO.sub.2  .sub.----CH.sub.3 : 3.18(s,3H),                                  CHO: 8.19(s,1H)    26      3.32    2.27    1.56  4"-SO.sub.2 CH.sub.3 : 3.04(s,3H),                                  11-SO.sub.2 CH.sub.3 : 3.15(s,3H)    __________________________________________________________________________     In Table 3, Ac is acetyl and Phe is phenyl.

REFERENCE EXAMPLE 23

200 mg of 8,9-anhydroerythromycin A 6,9-hemiketal (compound 27) (V. C.Stephens et al., Antibiotics Annual, 1958-1959, 346) was dissolved in3.4 ml of CHCl₃, then added with 0.22 ml of anhydrous pyridine and 0.34ml of butyric anhydride, and was allowed to stand for 20 minutes at roomtemperature. The reaction solution was diluted with 20 ml of CHCl₃, andwashed with 20 ml of the saturated aqueous solution of sodium hydrogencarbonate and 20 ml of water. The CHCl₃ layer was dried with anhydroussodium sulfate, and concentrated under a reduced pressure to obtain acolorless glas-like substance. Said substance was purified by silica gelcolumn chromatography, utilizing a developing mixed solvent of CHCl₃:CH₃ OH:conc. NH₄ OH=40:1:0.01, to obtain 209 mg (yield 95.2%) of2'-0-butyryl-8,9-anhydroerythromycin A 6,9-hemiketal (compound 28) inwhite powder.

Rf value: 0.36 (CHCl₃ :CH₃ OH:conc. NH₄ OH=10: 1:0.01) Carrier:silicagel (Merck, est Germany), High mass: 785.4936 (calcd. for C₄₁ H₇₁ NO₁₃:785.4921).

The same carrier was employed also in the thin layer chromatography inthe following Examples.

REFERENCE EXAMPLE 24

200 mg of 2'-0-acetyl-8,9-anhydroerythromycin A 6,9-hemiketal (compound29) (V. C. Stephens et al., Antibiotics Annual, 1958-1959, 346) wasdissolved in 4 ml of anhydrous pyridine, and added with 0.12 ml ofmethanesulfonyl chloride under cooling with ice. After 30 minutes, thesame process as that for producing the compound 28 was conducted toobtain a colorless glas-like substance. This substance was dissolved,without purification in 8 ml of methanol and was let to stand at roomtemperature. After one day, the reaction solution was concentrated underreduced pressure to obtain a colorless glass-like substance. Thissubstance was purified by silica gel column chromatography, utilizing amixed developing solvent of CHCl₃ :CH₃ OH:conc. NH₄ OH=30:1:0.01, toobtain 116 mg (yield 52.3%) of4"-0-methanesulfonyl-8,9-anhydroerythromycin A 6,9-hemiketal (compound30) in white powder.

Rf value: 0.20 (CHCl₃ :CH₃ OH:conc. NH₄ OH=10:1 :0.01), high mass:793.427 (calcd. for C₃₈ H₆₇ NO₁₄ S: 793.427).

REFERENCE EXAMPLE 25

300 mg of 2'-0-acetyl-4"-0-formyl-8,9-anhydroerythromycin A6,9-hemiketal (compound 31) (=compound 8) (Journal of The ChemicalSociety, 39, 2495, 1974) was dissolved in 8.1 ml of CHCl₃, and heatedunder reflux with 5 mg of 4-dimethylaminopyridine, 15 ml oftriethylamine and 1.2 ml of acetic anhydride. The reaction mixture wascooled to room temperature after 3 days, and the same process as thatfor obtaining the compound 28 was conducted to obtain a pale yellowglass-like substance. This substance was dissolved, withoutpurification, in 12 ml of methanol, and heated under reflux. Thesolution was cooled to room temperature after 3 days and concentratedunder reduced pressure to obtain a pale yellow glass-like substance.This substance was purified by silica gel column chromatography,utilizing a developing solvent system of CHCl₃ :CH₃ OH: conc. NH₄OH=50:1:0.01, to obtain 136 mg (yield 44.5%) of 11,12-di-0-acetyl-8,9-anhydroerythromycin A 6,9-hemiketal (compound 32) in whitepowder.

Rf value: 0.15 (CHCl₃ :CH₃ :conc. NH₄ OH=10:1 :0.01), low mass: M+799,high mass: 799.4703 (calcd. for C₄₁ H₆₉ NO₁₄ : 799.4713).

REFERENCE EXAMPLE 26

300 mg of the compound 31 was dissolved in 8.1 ml of CHCl₃, then addedwith 5 mg of 4-dimethylaminopyridine, 2.2 ml of triethylamine and 2.2 mlof propionic anhydride, and processed in the same manner as in thepreparation of the compound 32 to obtain 68 mg (yield 21.5%) of11,12-di-0-propionyl-8,9-anhydroerythromycin A 6,9-hemiketal (compound33) in white powder.

Rf value: 0.16 (CHCl₃ :CH₃ OH:conc. NH₄ OH=10:1 :0.01), high mass:827.502 (calcd. for C₄₃ H₇₃ NO₁₄ : 827.502).

REFERENCE EXAMPLE 27

300 mg of the compound 31 was dissolved in 8.1 ml of CHCl₃, then addedwith 5 mg of 4-dimethylaminopyridine, 2.2 ml of triethylamine and 2.6 mlof butyric anhydride, and processed in the same manner as in thepreparation of the compound 32 to obtain 141 mg (yield 43.2%) of11,12-di-0-butyryl-8,9-anhydroerythromycin A 6,9-hemiketal (compound 34)in white powder.

Rf value: 0.18 (CHCl₃ :CH₃ OH:conc. NH₄ OH=10:1 :0.01), low mass: M⁺855, high mass: 855.5343 (calcd. for C₄₅ H₇₇ NO₁₄ :855.5339).

REFERENCE EXAMPLE 28

1.0 g of the compound 31 was dissolved in 10 ml of toluene, and heatedunder reflux with 929 mg of thiocarbonyl diimidazole. The solution wascooled to room temperature after 4 hours and processed in the samemanner as in the preparation of the compound 28 to obtain a yellowglass-like substance. The obtained glass-like substance was purified bysilica gel column chromatography, utilizing a developing solvent systemof CHCl₃ :CH₃ OH:conc. NH₄ OH=100:1: 0.01, to obtain 373 mg (yield36.0%) of 2'-0-acetyl-4"-0-formyl-8,9-anhydroerythromycin A6,9-hemiketal-cyclic-11,12-thiocarbonate (compound 35) in white powder.

Rf value: 0.45 (CHCl₃ :CH₃ OH:conc. NH₄ OH=10:1 :0.01), high mass:827.4091 (calcd. for C₄₁ H₆₅ NO₁₄ S: 827.4121).

REFERENCE EXAMPLE 29

100 mg of the compound 35 was dissolved in 4 ml of methanol and heatedunder reflux. After 3 days, the solution was cooled to room temperature,and concentrated under reduced pressure to obtain a colorless glass-likesubstance. The obtained glass-like substance was purified by silica gelcolumn chromatography, utilizing a developing solvent system of CHCl₃:CH₃ OH:conc. NH₄ OH=50:1: 0.01, to obtain 63 mg (yield 68.8%) of8,9-anhydroerythromycin A 6,9-hemiketal-cyclic-11,12-thiocarbonate(compound 36) in white powder.

Rf value: 0.20 (CHCl₃ :CH₃ OH:conc. NH₄ OH=10:1 :0.01), high pass757.4061 (calcd. for C₃₈ H₆₃ NO₁₂ S: 757.407).

REFERENCE EXAMPLE 30

170 mg of the compound 27 was dissolved in 1.1 ml of methanol, thenadded with 213 mg of potassium carbonate and 27 μl of ethylene sulfiteand agitated at room temperature. After 2 days, the solution wasprocessed in the same manner as in the preparation of the compound 28 toobtain a colorless glass-like substance. The obtained glass-likesubstance was purified by silica gel column chromatography, utilizing adeveloping solvent system of CHCl₃ :CH₃ OH: conc. NH₄ OH=10:1:0.01, toobtain 72 mg (yield 39.8%) of 8,9-anhydroerythromycin A6,9-hemiketal-11,12-sulfite (compound 37) in white powder.

Rf. value: 0.09 (CHCl₃ :CH₃ OH:conc. NH₄ OH=10:1 :0.01), high mass:761.401 (calcd. for C₃₇ H₆₃ NO₁₃ S: 761.401).

REFERENCE EXAMPLE 31

200 mg of the compound 29 was dissolved in 10 ml of benzene, and heatedunder reflux with 32 mg of phenylboric acid. The solution was cooled toroom temperature after 2 hours and processed in the same manner as inthe preparation of the compound 28 to obtain 216 mg (yield 97.8%) of2'-0-acetyl-8,9-anhydroerythromycin A 6,9-hemiketal-11,12-phenylboronate(compound 38) in white powder.

This compound was so pure that it did not require purification.

Rf value: 0.40 (CHCl₃ :CH₃ OH:conc. NH₄ OH=10:1:0.01).

REFERENCE EXAMPLE 32

216 mg of the compound 38 obtained in Reference Example 31 was dissolvedin 8.6 ml of methanol and was let to stand at room temperature. After 1day, the solution was concentrated under a reduced pressure to obtain acolorless glass-like substance. The obtained glasslike substance waspurified by silica gel column chromatography, utilizing a developingsolvent system of CHCl₃ :CH₃ OH:conc. NH₄ OH=50:1:0.01, to obtain 199 mg(yield 97.0%) of 8,9-anhydroerythromycin A6,9-hemiketal-11,12-phenylboronate (compound 39) in white powder.

Rf value: 0.40 (CHCl₃ :CH₃ OH:conc. NH₄ OH=10:1:0.01).

REFERENCE EXAMPLE 33

1.40 g of the compound 29 was dissolved in 14 ml of dry pyridine, thenadded with 1.1 ml of chlorotrimethylsilane and was let to stand at roomtemperature. After 2 hours, the solution was processed in the samemanner as in the preparation of the compound 28 to obtain 1.50 g (yield90.0%) of 2'-0-acetyl-11,4"-di-0-trimethylsilyl-8,9-anhydroerythromycinA 6,9-hemiketal (compound 40) as acolorless glass-like substance.

Rf value: 0.43 (CHCl₃ :CH₃ OH:conc. NH₄ OH=10:1:0.01).

REFERENCE EXAMPLE 34

750 mg of the compound 40 was dissolved in 3 ml of 1,2-dichloromethane,then added with 2.40 g of tribenzylamine and 0.72 ml of acetayl chlorideunder cooling, and, after cooling 10 minutes, heated at 75° underagitation. After 3 days, the solution was processed in the same manneras in the preparation of the compound 28 to obtain a pale yellow solidsubstance. The obtained solid substance was dissolved, withoutpurification, in 30 ml of methanol and heated at 50° C. The solution wascooled to room temperature after 1 day and concentrated under a reducedpressure to obtain a pale yellow solid substance. The obtained solidsubstance was purified by silica gel column chromatography, utilizing adeveloping solvent system of CHCl₃ :CH₃ OH: conc. NH₄ OH=50:1:0.01, toobtain 163 mg (yield 25.9%) 25.9%) of12-0-acetyl-8,9-anhydroerythromycin A 6,9-hemiketal (compound 41) aswhite powder.

Rf value: 0.15 (CHCl₃ :CH₃ OH:conc. NH₄ OH=10:1:0.01), high mass:757.460 (calcd. for C₃₉ H₆₇ NO₁₃ : 757.460)

REFERENCE EXAMPLE 35

800 mg of the compound 40 was dissolved in 3.2 ml of 1,2-dichloroehane,then added with 2.56 g of tribenzylamine and 0.85 ml of propionylchloride under cooling, and, after 10 minutes, heated at 75° C. underagitation. After 3 dayts, the solution was processed in the same manneras in the preparation of the compound 30 to obtain 273 mg (yield 39.(%)of 12-0-propionyl-8,9-anhydroerythromycin A 6,9-hemiketal (compound 42)as white powder.

Rf value: 0.17 (CHCl₃ :CH₃ OH:conc. NH₄ OH=10:1:0.01), high mass:771.476 (calcd. for C₄₀ H₆₉ NO₁₃ : 771.476).

REFERENCE EXAMPLE 36

400 mg of the compound 29 was dissolved in 0.8 ml of dichloromethane,then added with 0.2 ml of N,N-diisopropylethylamine and 0.22 ml ofmethoxyethoxy methyl chloride under cooling, and, after 10 minutes, waslet to stand at room temperature. After 3 hours, the same process as inthe preparation of the compound 28 as conducted to obtain a colorlessglass-like substance. The obtained glass-like substance was purified bysilica gel column chromatography, utilizing a developing solvent systemof CHCl:CH₃ OH: conc. NH₄ OH=100:1:0.01, to obtain 250 mg (yield 56.0%)of 2'-10-acetyl-4"-0-methoxyethoxymethyl-8,9-anhydroerythromycin A6,9-hemiketal (compound 43) as white powder.

Rf value: 0.43 (CHCl₃ :CH₃ OH:conc. NH₄ OH=10:1:0.01), high mass:845.513 (calcd. for C₄₃ H₇₅ NO₁₅ : 845.513).

REFERENCE EXAMPLE 37

150 mg of the compound 43 obtained in Example 36 was dissolved in 6 mlof methanol and was let to stand at room temperature. After one day, thereaction solution was concentrated under reduced pressure to obtain acolorless glass-like substance. The obtained glass-like substance waspurified by silica gel column chromatography, utilizing a developingsolvent system of CHCl₃ :CH₃ OH:conc. NH₄ OH=30:1:0.01, to obtain 85 mg(yield 59.6%) of 4"-0-methoxy-ethoxymetyyl-8,9-anhydroerythromycin A6,9-hemiketal (compound 44) in white powder.

Rf value: 0.27 (CHCl₃ :CH₃ OH:conc. NH₄ OH=10:1:0.01), high mass:803.502 (calcd. for C₄₁ H₇₃ NO₁₄ : 803.502).

The structure, speicific rotatory power and NMR spectrum of thecompounds obtained in Reference Examples 23 -37 are summarized in Tables4 and 5.

                                      TABLE 4    __________________________________________________________________________     ##STR99##    Compound    No.   R.sup.1  R.sup.2    R.sup.5  R.sup.6  [α].sub.D.sup.23 (                                                -c1.0, CHCl.sub.3)    __________________________________________________________________________    28    CH.sub.3 CH.sub.2 CH.sub.2 CO                   H          H        H        -37.4°    30    H        CH.sub.3 SO.sub.2                              H        H        -44.6°    32    H        H          CH.sub.3 CO                                       CH.sub.3 CO                                                -30.0°    33    H        H          CH.sub.3 CH.sub.2 CO                                       CH.sub.3 CH.sub.2 CO                                                -22.0°    34    H        H          CH.sub.3 CH.sub.2 CH.sub.2 CO                                       CH.sub.3 CH.sub.2 CH.sub.2 CO                                                -19.0°    35    CH.sub.3 CO                   CHO                               ##STR100##        +8.6°    36    H        H                               ##STR101##       +25.0°    37    H        H                               ##STR102##       -30.2°    38    CH.sub.3 CO                   H                               ##STR103##       -54.0°    39    H        H                               ##STR104##       -60.2°    40    CH.sub.3 CO                   (CH.sub.3).sub.3 Si                              (CH.sub.3).sub.3 Si                                       H    41    H        H          H        CH.sub.3 CO                                                -35.6°    42    H        H          H        CH.sub.3 CH.sub.2 CO                                                -65.2° ( -c 0.5)    43    CH.sub.3 CO                   CH.sub.3 OCH.sub.2 CH.sub.2 OCH.sub.2                              H        H        -30.4°    44    H        CH.sub.3 OCH.sub.2 CH.sub.2 OCH.sub.2                              H        H        -34.0°    __________________________________________________________________________     In Table 4 Ph is phenyl, Si is sylyl.     The number of compounds correspond to those in Reference Examples.

                                      TABLE 5    __________________________________________________________________________    .sup.1 H-NMR peak (δ value ppm, solvent CDCl.sub.3)    Com-    pound    No. 8-Me(s,3H)              3'-NMe.sub.2 (s,6H)                      3"-OMe(s,3H)                              Others    __________________________________________________________________________    28  1.51  2.25    3.20    30  1.56  2.28    3.32    4"-SCH.sub.3 3.08(s,3H)    32  1.53  2.20    3.34    12-COCH.sub.3 2.04(s,3H), 11-COCH.sub.3,                              2.14(s,3H)    33  1.52  2.28    3.34    34  1.48  2.24    3.30    35  1.58  2.28    3.34    2'-COCH.sub.3 2.00(s,3H), 4"-CHO 8.28(s,1H)    36  1.58  2.28    3.25    37  1.57  2.29    3.20    38  1.57  2.31    3.35    B-Ph 7.4˜7.9(m,5H), 2'-COCH.sub.3                              2.07(s,3H)    39  1.63  2.33    3.39    B-Ph 7.4˜7.9(m,5H)    41  1.51  2.20    3.31    12-COCH.sub.3 1.98(s,3H)    42  1.56  2.32    3.32    43  1.55  2.26    3.38    2-COCH.sub.3 2.04(s,3H),OCH.sub.2 OCH.sub.2                              CH.sub.2 OCH.sub.3 3.38(s,3H),4.83(s,2H)    44  1.56  2.27    3.32    OCH.sub.2 OCH.sub.2 CH.sub.2 OCH.sub.3                              3.38(s,3H), 4.83(s,2H)    __________________________________________________________________________

REFERENCE EXAMPLE 38

300 mg of the compound 27 was dissolved in 3 ml of dry pyridine, amdadded with 0.4 ml of acetic anhydride. The reaction mixture was heatedat 50° C. for 24 hours. The reaction solution as poured into 10 ml ofthe cold saturated aqueous solution of sodium hydrogen carbonate, andthe resulting product was extracted with chloroform (3×10 ml). Theextracting solution was dried with anhydrous sodium sulfate, and thesolvent was removed under reduced pressure to obtain a crude product.This product was purified by silica gel column chromatography (Merck Art7734 silica gel 20 g; eluting solvent chloroform-methanol [50: 1)] toobtain 290 mg of 11,2', 4"-tri-0-acetyl-8,9-anhydroerythromycin A6,9-hemiketal (compound 45) as white powder.

Rf value: 0.38 (CHCl₃ :CH₃ OH=20:1).

REFERENCE EXAMPLE 39

290 mg of the compound 45 obtained in Reference Example 38 was dissolvedin 3 ml of dry dimethyl sulfoxide, and added with 1 ml. of aceticanhydride. The reaction mixture was let to stand for 96 hours at roomtemperature. The reaction solution was concentrated under reducedpressure (<2 mm Hg), and the residue was dissolved in 20 ml ofchloroform. The obtained chloroform solution was washed with 10 ml ofthe saturated aqueous solution of sodium hydrogen carbonate, then driedwith anhydrous sodium sulfate, and the solvent was distilled off underreduced pressure. The crude produce was purified by silica gel columnchromatography (Merck Art 7734 silica gel 20 g.; eluting solventchloroform-methanol (50:1)), to obtain 173 mg of11,2',4"-tri-0-acetyl-12-0-methylthiomethyl-8,9-anhydroerythromycin A6,9-hemiketal (compound 46) as white powder.

Rf value: 0.39 (CHCl₃ :CH₃ OH=20:1).

REFERENCE EXAMPLE 40

173 mg of the compound 46 obtained in Reference Example 39 was dissolvedin 5 ml of methanol, and added with 20 mg of lithium hydroxide. Thereaction solution was heated at 50° C. for 4 hours under agitation.After concentration under a reduced pressure, the residue was dissolvedin 20 ml of chloroform. The chloroform solution was washed with 10 ml ofwater, then was dried with anhydrous sodium sulfate, and the solvent wasdistilled off under reduced pressure. The crude product was purified bysilica el column chromatography (Merck Art 7734 silica gel 15 g; elutingsolvent:chloroform-methanol (30:1)), to obtain 118 mg of12-0-methylthiomethyl-8,9-anhydroerythromycin A 6,9-hemiketal (compound47) was white powder.

Rf value: 0.16 (CHCl₃ :CH₃ OH=10:1).

REFERENCE EXAMPLE 41

300 mg of the compound 8 was dissolved in 3 ml of dry pyridine, andadded with 0.3 ml of acetic anhydride. The mixture was heated at 50° C.for 24 hours. The reaction solution was poured into 10 ml of the coldsaturated aqueous solution of sodium hydrogen carbonate, and theresulting product was extracted with chloroform (3×10 ml). Theextracting solution was dried with anhydrous sodium sulfate, and thesolvent was distilled off under reduced pressure to obtain a crudeproduct. This product was purified by silica gel column chromatography[Merck Art 7734 silica gel 20 g, eluting solvent : chloroform-methanol(50:1)] to obtain 195 mg of 11,2'-di-0-acetyl-4"-0-formyl-8,9-anhydroerythromycin A 6,9-hemiketal (compound 48) as white powder.

Rf value: 0.37 (CHCl₃ :CH₃ =10:1) high mass: 827.4680 (calcd. for C₄₂H₆₉ NO₁₅ :827.4663).

REFERENCE EXAMPLE 42

195 mg of the compound 48 obtained in Example 41 was dissolved in 5 mlof methanol, and the solution was heated under reflux for 1 hour. Thenthe solvent was distilled off under a reduced pressure to obtain a crudeproduct. This product was purified by silica gel column chromatography(Merck Art 7734 silica gel 20 g, eluting solvent : chloroform-methanol(30 : 1)) to obtain 155 mg of11-0-acetyl-4"-0-formyl-8,9-anhydroerythromycin A 6,9-hemiketal(compound 49) as white powder.

Rf value: 0.28 (CHCl₃ :CH₃ CH₃ CH=10:1)

REFERENCE EXAMPLE 43

210 mg of the compound 48 obtained in Reference Example 41 was dissolvedin 5 ml of methanol, and the solution was heated under reflux for 45hours. Then the solvent was distilled off under reduced pressure toobtain a crude product. This product was purified by silica gel columnchromatography (Merck Art 7734 silica gel 20 g, eludingsolvent:chloroform-methanol (30:1)) to obtain 158 mg of11-0-acetyl-8,9-anhydroerythromycin A 6,9-hemiketal (compound 50) aswhite powder.

Rf value: 0.21 (CHCl₃ :CH₃ OH=10:1).

REFERENCE EXAMPLE 44

155 mg of the compound 49 obtained in Reference Example 42 was processedin the same manner as in Example 43 to obtain 115 mg of11-0-actyl-8,9-anhydroerythromycin A 6,9-hemiketal (compound 50) aswhite powder.

REFERENCE EXAMPLE 45

300 mg of the compound 8 was dissolved in 3 ml of dry pyridine, andadded with 0.3 ml of acetic anhydride. The reaction mixture was heatedat 50° C. for 24 hours. The reaction solution was poured into 10 ml ofthe cold saturated aqueous solution of sodium hydrogen carbonate, andthe resulting product was extracted with chloroform (3×10 ml). Theextract was dried with anhydrous sodium sulfate, and the solvent wasdistilled off under reduced pressure. The residue was dissolved in 5 mlof methanol, and heated under reflux for 45 hours. The solvent wasdistilled off under reduced pressure, and the residue was purified bysilica gel column chromatography to obtain 156 mg of11-0-acetyl-8,9-anhydroerythromycin A 6,9-hemiketal (compound 50) aswhite powder.

REFERENCE EXAMPLE 46

300 mg of the compound 8 and 0.3 ml of propionic anhydride were reactedaccording to the method of Reference Example 45,. and the protection wasremoved with methanol. The crude product was purified by silica gelcolumn chromatography (Merck Art 7734 silica gel 20 g, elutingsolvent:chloroform-methanol (30:1 )) to obtain 152 mg of 11-0-propionyl-8,9-anhydroerythromycin A 6,9-hemiketal (compound 51) as whitepowder.

Rf value: 0.21 (CHCl₃ :CH₃ OH)=10:1).

REFERENCE NUMERAL 47

300 mg of the compound 8 and 0.3 ml of butyric anhydride were reactedand after removal of the protection according to the process ofReference Example 45, a crude product was obtained. This product waspurified by silica gel column chromatography (Merck Art 7734 silica gel20 g, eluting solvent:chloroform-methanol (30:1) to obtain 146 mg of11-0-butyryl-8,9-anhydroerythromycin A 6,9-hemiketal (compound 52) aswhite powder.

Rf value: 0.21 (CHCl3:CH₃ OH=10:1)

REFERENCE EXAMPLE 48

300 mg of the compound 8 and 0.3 ml of benzoyl chloride were reacted andafter removal of the protection according to the process of ReferenceExample 45, a crude product was obtained. This product was purified bysilica gel column chromatography (Merck Art 7734 silica gel 20 g,eluting solvent:chloroform-methanol (30:1)) to obtain 155 mg of11-0-benzoyl-8,9-anhydroerythromycin A 6,9-hemiketal (compound 53) aswhite powder;

Rf value: 0.20 (CHCl₃ :CH₃ OH=10:1)

REFERENCE EXAMPLE 49

200 mg of erythromycin A was dissolved in 2 ml of CHCl₃, then added with78 μl of 2-methoxypropene and 64 mg of pyridinium chloride and let tostand at room temperature. After 1 day, the reaction solution wasdiluted with 20 ml of CHCl₃, and washed with 20 ml of the saturatedaqueous solution of sodium hydrogen carbonate and 20 ml of water. TheCHCl₃ layer was dried with anhydrous sodium sulfated and concentratedunder a reduced pressure to obtain a colorless glass-like substance. Theobtained glass-like substance was purified by silica gel columnchromatography, utilizing a developing solvent system of CHCl₃ :CH₃OH:conc. NH₄ OH=30:1:0.01, to obtain 194 mg (94.0%) of11,12-0-isopropylidene-8,9-anhydroerythromycin A 6,9-hemiketal (compound54) as colorless powder.

Rf value: 0.14 (CHCl₃ :CH₃ OH:conc. NH₄ OH=10: 1:0.01), high mass :755.4856 (calcd. for C₄₀ H₆₉ NO₁₂ :755.4815).

The structure, specific rotatory power and NMR spectrum of the compoundsobtained in Examples 38-49 are summarized in Tables 6 and 7.

                                      TABLE 6    __________________________________________________________________________     ##STR105##    Compound    No.   R.sup.1              R.sup.2                  R.sup.5  R.sup.6                                 [α].sub.D.sup.23 ( -c1.0,CHCl.sub.3)    __________________________________________________________________________    45    CH.sub.3 CO              CH.sub.3 CO                  CH.sub.3 CO                           H     -30.6°    46    CH.sub.3 CO              CH.sub.3 CO                  CH.sub.3 CO                           CH.sub.3 SCH.sub.2                                 -31.6°    47    H   H   H        CH.sub.3 SCH.sub.2                                 -28.6°    48    CH.sub.3 CO              CHO CH.sub.3 CO                           H     -25.6°    49    H   CHO CH.sub.3 CO                           H     -18.6°    50    H   H   CH.sub.3 CO                           H     -18.0°    51    H   H   CH.sub.3 CH.sub.2 CO                           H     -19.2°    52    H   H   CH.sub.3 CH.sub.2 CH.sub.2 CO                           H     -20.4°    53    H   H   PhCO     H     -38.0°    54    H   H                   ##STR106##    -24.8°    __________________________________________________________________________     In the Table 6, Ph is phenyl.     The numbers of compounds correspond to those in Reference Examples.

                                      TABLE 7    __________________________________________________________________________    .sup.1 H-NMR peak (δ value ppm, solvent CDCl.sub.3)    Com-    pound    No. 8-Me(s,3H)              3'-NMe.sub.2 (s,6H)                      3"-OMe(s,3H)                              Others    __________________________________________________________________________    45  1.56  2.30    3.35    2'-COCH.sub.3 2.06(s,3H),4"-COCH.sub.3 2.10(s,3H                              ),11-COCH.sub.3,2.12(s,3H)    46  1.57  2.29    3.35    2'-COCH.sub.3 2.05(s,3H),4"-COCH.sub.3 2.08(s,3H                              ),11-COCH.sub.3,                              2.10(s,3H), 12CH.sub.2 SCH.sub.3,2.19(s,3H)    47  1.54  2.30    3.29    12-CH.sub.2 SCH.sub.3 2.19(s,3H)    48  1.57  2.28    3.37    2'-OAc 2.05(s,3H),11-OAc 2.12(s,3H),4"-OCHO                              8.20(s,1H)    49  1.58  2.30    3.35    11-OAc 2.12(s,3H),4"-OCHO 8.20(s,1H)    50  1.58  2.31    3.36    11-OAc 2.13(s,3H)    51  1.58  2.31    3.35    52  1.58  2.31    3.35    53  1.58  2.34    3.36    11-OBz 7.43 (m,3H), 8.05(m,2H)    __________________________________________________________________________     In Table 7, Ac is acetyl and Bz is benzoyl.

REFERENCE EXAMPLE 50

100 mg of the compound 27 was dissolved in 1 ml of chloroform andstirred for 2 hours with addition of 40 μl of methyl iodide. After mostof the solvent was distilled off, 5 ml of ether was added and theprecipitate formed was filtered. The precipitate was washed with etherand dried to obtain 65 mg (yield 54%) of 8,9-anhydroerythromycin A6,9-hemiketal methyl iodide (compound 55) in white powder.

REFERENCE EXAMPLE 51

By using 30 mg of the compound 32 and 15 μl of methyl iodide, the sameprocessing as in Reference Example 50 was conducted to obtain 18 mg(yield 51%) of 11,12-di0-acetyl-8,9-anhydroerythromycin A 6,9-hemiketalmethyl iodide (compound 56) in white powder.

REFERENCE EXAMPLE 52

By using 79 mg of 11,0-methanesulfonyl-8,9-anhydroerythromycin A6,9-hemiketal (compound 57) and 29 μl of methyl iodide, the sameprocessing as in Reference Example 50 was conducted to obtain in 55 mg(yield 58%) of 11-0-methanesulfonyl-8,9-anhydroerythromycin A6,9-hemiketal methyl iodide (compound 58) in white powder.

REFERENCE EXAMPLE 53

By using 78 mg of the compound 25 and 59 μl of methyl iodide, the sameprocessing as in Reference Example 50 was conducted to obtain 67 mg(yield 74%) of 11-0-methane-sulfonyl-4"-0-formyl-8,9-anhydroerythromycinA 6,9-hemiketal methyl iodide (compound 59) in pale yellow powder.

REFERENCE EXAMPLE 54

200 mg of the compound 27 was dissolved in 4 μl of chloroform, then 0.5ml of ethyl iodide was added thereto and the mixture was refluxed for 20hours. After most of the solvent was distilled off under reducedpressure, 10 ml of ether was added and a precipitate formed wasfiltered. The precipitate was washed with ether and dried to obtain 145mg (yield 60%) of 8,9-anhydroerythromycin A 6,9-hemiketal ethyl iodide(compound 60) in white powder.

REFERENCE EXAMPLE 55

200 mg of the compound 27 was dissolved in 4 ml of chloroform, then 0.5ml of propyl iodide was added thereto and the mixture was refluxed for48 hours. After the same processing as in Reference Example 54, 120 mg(yield 48%) of 8,9-anhydroerythromycin A 6,9-hemiketal propyl iodide(compound 61) was obtained in white powder.

REFERENCE EXAMPLE 56

200 mg of the compound (1) and 0.2 ml of methyl iodide were employed tocarry out the same processing as in Reference Example 50. As the result,154 mg (yield 65%) of 2'-0-acetyl-8,9-anhydroerythromycin A6,9-hemiketal methyl iodide (compound 62) was obtained in white powder.

The structural formulae of the compounds obtained Reference 50 to 56 andtheir physical properties are shown in Table 8 and Table 9,respectively.

                                      TABLE 8    __________________________________________________________________________     ##STR107##    Compound No.            R.sup.1                 R.sup.2                     R.sup.5                          R.sup.6                               R.sup.e                                      R.sup.f                                         X    __________________________________________________________________________    55      H    H   H    H    CH.sub.3                                      CH.sub.3                                         I    56      H    H   CH.sub.3 CO                          CH.sub.3 CO                               CH.sub.3                                      CH.sub.3                                         I    58      H    H   CH.sub.3 SO.sub.2                          H    CH.sub.3                                      CH.sub.3                                         I    59      H    CHO CH.sub.3 SO.sub.2                          H    CH.sub.3                                      CH.sub.3                                         I    60      H    H   H    H    CH.sub.3 CH.sub.2                                      CH.sub.3                                         I    61      H    H   H    H    CH.sub.3 CH.sub.2 CH.sub.2                                      CH.sub.3                                         I    62      CH.sub.3 CO                 H   H    H    CH.sub.3                                      CH.sub.3                                         I    __________________________________________________________________________

                                      TABLE 9    __________________________________________________________________________          specific    Compound          rotary   NMR spectrum δ value ppm    No.   power    8-Me(s,3H)                         3'-NMe                              3"-OMe(s,3H)                                      others(solvent)    __________________________________________________________________________    55    [α].sub.D.sup.23 -28.6°                   1.58  3.64 3.49    (CDCl.sub.3)          ( -c = 1.0,CHCl.sub.3)                         (s,9H)    56    [α].sub.D.sup.23 -25.4°                   1.51  3.48 3.37    1.99(11-COCH.sub.3,s,3H),          ( -c = 1.0,CHCl.sub.3)                         (s,9H)       2.03(12-COCH.sub.3,s,9H)                                      (CDCl.sub.3)    58    [α].sub.D.sup.23 -22.2°                   1.59  3.35 3.43    3.18(SO.sub.2 CH.sub.3,s,3H)          ( -c = 1.0,CH.sub.3 OH)                         (s,9H)       (CDCl.sub.3)    59    [α].sub.D.sup.23 -24.8°                   1.58  3.34 3.54    3.16(SO.sub.2 CH.sub.3,s,3H)          ( -c = 1.0,CHCl.sub.3)                         (s,9H)       8.28(CHO,s,1H)                                      (CDCl.sub.3)    60    [α].sub.D.sup.23 -27.8°                   1.59  3.19 3.38    (CD.sub.3 OD)          ( - c = 1.0,CH.sub.3 OH)                         (s,6H)    61    [α].sub.D.sup.23 -28.4°                   1.58  3.12 3.38    (CD.sub.3 OD)          ( -c = 1.0,CH.sub.3 OH)                         (s,6H)    62    [α].sub.D.sup.23 -29.2°                   1.58  3.22 3.40    2.19(2'-O-COCH.sub.3,s,3H)          ( -c = 1.0,CH.sub.3 OH)                         (s,9H)       (CD.sub.3 OD)    __________________________________________________________________________

REFERENCE EXAMPLE 57

100 mg of the compound 27 was dissolved in 2 ml of dry ether and addedwith 73 μl of diisopropylethylamine and 33 μl of valeryl chloride at 0°.The mixture was warmed to room temperature, and stirred for 15 minutesat the same temperature, followed by dilution with addition of 25 ml ofethyl acetate. This was washed with the saturated aqueous sodiumhydrogen carbonate and saturated aqueous sodium chloride solution,followed by drying over anhydrous sodium sulfate. The crude produceobtained by evaporation of the solvent was purified by silica gelchromatography (developing solvant:chloroform-methanol-conc. aqueousammonia (20:1:0.01)) to obtain 96 mg (yield 86%) of 2'-0-varelyl-8,9-anhydroerythromycin A 6,9-hemiketal (compound 63) in white powder.

REFERENCE EXAMPLE 58

By using 50 mg of the compound 27, 37 μl of iisopropylethylamine and 20μl of hexanoyl chloride, the same processing as in Reference Example 57was conducted to obtain 53 mg (yield 94%) of2'-0-hexanoyl-8,9-anhydroerythromycin A 6,9-hemiketal (compound 64) inwhite powder.

REFERENCE EXAMPLE 59

By using 100 mg of the compound 27, 73 μl of diisopropylethylamine and93 mg of arachidonyl chloride, the same processing as in ReferenceExample 57 was conducted to obtain 104 mg (yield 73%) of2'-0-arachidonyl-8,9-anhydroerythromycin A 6,9-hemidetal (compound 65)in white powder.

REFERENCE EXAMPLE 60

By using 100 mg of the compound 27, 73 μl of diisopropylethylamine and34 ml of isovaleryl chloride, the same processing as in ReferenceExample 57 was conducted to obtain 100 mg (yield 89%) of2'-0-isovaleryl-8,9-anhydroery thromycin A 6,9-hemiketal (compound 66)in white powder.

REFERENCE EXAMPLE 61

By using 100 mg of the compound 27, 73 μl of diisopropylethylamine and27 μl of crotonyl chloride, the same processing as in Reference Example57 was conducted to obtain 87 mg (yield 79%) of2'-0-crotonyl-8,9-anhydroery thromycin A 6,9-hemiketal (compound 67) inwhite powder.

REFERENCE EXAMPLE 62

By using 100 mg of the compound 27, 73 μl of diisopropylethylamine and33 μl of benzoyl chloride, the same processing as in Reference Example57 was conducted to obtain 87 mg (yield 75%) of2'-0-benzoyl-8,9-anhydroerythromycin A 6,9-hemiketal (compound 68) inwhite powder.

REFERENCE EXAMPLE 63

200 mg of the compound 27 was dissolved in 4 ml of chloroform and 150 μlof diisopropylethylamine was added thereto After the mixture was heatedto 50° C., 32 μl of methanesulfonyl chloride was added thereto and themixture was stirred for 25 minutes, followed further by addition of 20μl of methanesulfonyl chloride. After stirring for 15 minutes, themixture was cooled to room temperature and diluted with 30 ml of ethylacetate. This was washed with saturated aqueous sodium hydrogencarbonate and saturated aqueous sodium chloride solution, and dried overanhydrous sodium sulfate. The residue obtained by evaporation of thesolvent was purified by silica gel chromatography (developing solvent:chloroform-methanol-conc. aqueous ammonia (60 : 1 : 0.01)) to obtain 53mg of 2'-0-methanesulfonyl-8,9-anhydroerythromycin A 6,9-hemiketal(compound 69) (yield 24%) and 52 mg (yield 21%) of11,2'-di-0-methanesulfony-8,9-anhydroerythromycin A 6,9-hemiketal(compound 70).

REFERENCE EXAMPLE 64

100 mg of the compound 27 was dissolved in 1 ml of dry pyridine, addedwith 0.3 ml of diphenylchlorophosphate and the mixture was stirredovernight. The mixture was diluted with 20 ml of ethyl acetate and thesolution washed with saturated aqueous sodium hydrogen carbonate andsaturated aqueous sodium chloride solution and was dried over anhydroussodium sulfate and the solvent was evaporated. The crude productobtained was purified by silica gel chromatography [developing solvent:chloroformmethanol-conc. aqueous ammonia (10:1:0.01)] to obtain 43 mg(yield 33%) of 2'-0-diphenylphosphoryl-8,9-anhydroerythromycin A6,9-hemiketal (compound 71) in white powder.

REFERENCE EXAMPLE 65

Using 100 mg of the compound 27, 1 ml of pyridine and 0.2 ml ofdiethylchlorophosphate, the same processing as in Reference Example 64was conducted to obtain 25 mg (yield 21%) of2'-0-diethylphosphoryl-8,9-anhydroerythromycin A 6,9-hemiketal (compound72) in white powder.

REFERENCE EXAMPLE 66

157 mg of the compound (8) was dissolved in 1 ml of dry pyridine, addedwith 0.2 ml of valeric acid anhydride and the mixture was stirred at 50°C. for 2 weeks. After the mixture was cooled to room temperature, it wasdiluted with 30 ml of ethyl acetate and washed with saturated aqueoussodium hydrogen carbonate and saturated aqueous sodium chloride solutionand dried over anhydrous sodium sulfate. The solvent was evaporated andthe residue obtained was dissolved in 6 ml of methanol, followed bystirring at 50° C. for 3 hours. After cooling to room temperature andaddition of 0.4 ml of 5% aqueous sodium hydrogen carbonate solution themixture was further stirred for 6 hours. After concentration to a volumeof about 2 ml, the concentrate was diluted with 30 ml of ethyl acetateand washed with saturated aqueous sodium chloride solution, followed bydrying over anhydrous sodium sulfate. The crude product obtained byevaporation of the solvent was purified by silica gel chromatography[developing solvent: chloroform-methanol-conc. aqueous ammonia (10 : 1 :0.1)]to obtain 91 mg (yield 57%) of 11-0-valeryl-8,9-anhydroerythromycinA 6,9-hemiketal (compound 73) in white powder.

REFERENCE EXAMPLE 67

By using 157 mg of the compound 8,1 ml of dry pyridine and 0.2 ml ofhexanoic acid anhydride, the same processing as in Reference Example 66was conducted to obtain 98 mg (yield 60%) of11-0-hexanoyl-8,9-anhydroerythromycin A 6,9-hemiketal (compound 74) inwhite powder.

The structural formulae, specific rotatory powers and NMR spectrumvalues of the compounds obtained in Reference Examples 57-67 shown inTable 10.

                                      TABLE 10    __________________________________________________________________________     ##STR108##    compound               [α].sub.D.sup.23                                  .sup.1 H-NMR (δ value, CDCl.sub.3)    No.   R.sup.1  R.sup.2 ( -c1.0,CHCl.sub.3)                                  8-Me(s,3H)                                        3-NMe.sub.2 (s,6H)                                                3"-OMe(s,3H)                                                        others    __________________________________________________________________________    63    CO(CH.sub.2).sub.3 CH.sub.3                   H       -39.2°                                  1.55  2.25    3.38    64    CO(CH.sub.2).sub.4 CH.sub.3                   H       -39.8°                                  1.56  2.23    3.38    65    CO(CH.sub.2).sub.18 CH.sub.3                   H       -20.4°                                  1.55  2.25    3.38    66 67 COCH.sub.2 CH(CH.sub.3).sub.2 COCHCHCH.sub.3                   H H     -37.2° -44.6°                                  1.55 1.54                                        2.24 2.28                                                3.37 3.39                                                         ##STR109##    68    COPh     H       -43.6°                                  1.52  2.30    3.46    Ph: 7.45(m,3H),                                                        8.00(m,2H)    69    SO.sub.2 CH.sub.3                   H       -29.2°                                  1.57  2.30    3.35    SO.sub.2 CH.sub.3 :                                                        3.17(s,3H)    70    SO.sub.2 CH.sub.3                   SO.sub.2 CH.sub.3                           -24.0°                                  1.58  2.30    3.34    SO.sub.2 CH.sub.3 :                                                        3.17(s,3H)    71    PO(OPh).sub.2                   H       -42.4°                                  1.57  2.33    3.37    Ph: 7.23(m,10H)    72    PO(OEt).sub.2                   H       -42.4°                                  1.56  2.28    3.32    73    H        CO(CH.sub.2).sub.3 CH.sub.3                           -20.4°                                  1.57  2.20    3.35    74    H        CO(CH.sub.2).sub.4 CH.sub.3                           -17.8°                                  1.57  2.30    3.35    __________________________________________________________________________

REFERENCE EXAMPLE 68

1.00 g of de(N-methyl) erythromycin A (reference: Japanese Laid-openPatent Application No. 9129/1972) was dissolved in 5 ml of glacialacetic acid and the solution was stirred for 1 hour. The reactionmixture was poured into 20 ml of ice-cooled conc. aqueous ammonia. Themixture was extracted 3 times with 10 ml of chloroform. The chloroformsolution was dried over anhydrous sodium sulfate, and the solvent wasevaporated under reduced pressure. The residue was purified by silicagel chromatography [developing solvent: chloroformmethanol-conc. aqueousammonia (10:1:0.1)] to obtain 830 mg (yield 85%) ofde(N-methyl)-8,9-anhydroerythromycin A 6,9-hemiketal (compound 75) inwhite powder.

REFERENCE EXAMPLE 69

930 mg of bis-[de(N-methyl)] erythromycin A (reference: JapaneseLaid-open Patent Application No. 9129/1972) was processed in the samemanner as in Reference Example 68 to obtain 770 mg (yield 85%) of bis[de(N-methyl)]-8,9-anhydroerythromycin A 6,9-hemiketal (compound 76) inwhite powder.

REFERENCE EXAMPLE 70

400 mg of ethyl-nor-erythromycin A [reference: R. K. Clark. Jr. et al.Antibiotics and Chemotherapy VII, 483, (1957)] was processed in the samemanner as in Reference Example 68 to obtain 327 mg (yield 84%) ofethyl-nor-8,9-anhydroerythromycin A 6,9-hemiketal (compound 77) in whitepowder.

REFERENCE EXAMPLE 71

168 gm of butyl-nor-erythromycin A [reference: R. K. Clark, Jr. et al.Antibiotics and Chemotherapy VII, 483, (1957)] was processed in the samemanner as in Reference Example 68 to obtain 99 mg (yield 60%) ofbutyl-nor-8,9-anhydroerythromycin A 6,9-hemiketal (compound 78) in whitepowder.

EXAMPLE EXAMPLE 72

88 mg of the compound 77 was dissolved in 2 ml of chloroform, then 1 mlof ethyl iodide was added thereto and the mixture was stirred at 80° C.for 14 hours. After most of the solvent was evaporated under reducedpressure, 5 ml of ether was added and the precipitate formed wasfiltered. The precipitate was washed with ether and dried to obtain 72mg (yield 67%) of ethyl-nor-8,9-anhydroery- thromycin A 6,9-hemiketalethyl iodide (compound 79) in white powder.

REFERENCE EXAMPLE 73

376 mg of the compound 76 was dissolved in 5 ml of methanol. 138 mg ofsodium hydrogen carbonate and 1.0 ml of 1,4-dibromobuthane were added,and the mixture was stirred at 50° C. for 8 hours. The reaction mixturewas diluted with 30 ml of ethyl acetate, and washed with water andsaturated aqueous sodium chloride solution. The ethyl acetate solutionwas dried over anhydrous sodium sulfate and the solvent was evaporatedunder reduced pressure. The residue was purified by silica gel columnchromatography [eluant: chloroform-methanol-conc. aqueous ammonia (10:1:0.1)] to obtain 158 mg (yield 39%) ofde(dimethylamino)-3'-pyrrolidino-8,9-anhydroerythromycin A 6,9-hemiketal(compound 80) in white powder.

REFERENCE EXAMPLE 74

By using 63 mg of the compound 80 and 0.1 ml of methyl iodide, the sameprocessing as in Reference Example 50 was conducted to obtain 70 mg(yield 93%) of de(dimethylamino)-3'-pyrrolidino-8,9-anhydroerythromycinA 6,9-hemiketal methyl iodide (compound 81) in white powder.

REFERENCE EXAMPLE 75

120 mg of the compound 27 was dissolved in 1 ml of chloroform, then 0.5ml of 2-bromoethanol and 0.5 ml of diisopropylethylamine were addedthereto and the mixture was stirred for 2 days. After evaporation of thesolvent, 5 ml of ether was added and the precipitate formed wasfiltered. The precipitate was washed with 10 ml of ether and dried toobtain 119 mg (yield 84%) of 8,9-anhydroerythromycin A 6,9-hemiketal2-hydroxyethyl bromide (compound 82) in white powder.

REFERENCE EXAMPLE 76

150 mg of the compound 27 was dissolved in 1 ml of chloroform, then 0.5ml of allylbromide and 0.25 ml of diisopropylethylamine were addedthereto and the mixture was stirred for 1 day. After evaporation of thesolvent, 5 ml of ether was added and a precipitate formed was filtered.The precipitate was washed with 10 ml of ether and dried to obtain 134mg (yield 76%) of 8,9-anhydroerythromycin A 6,9-hemiketal allyl bromide(compound 83) in white powder.

The structural formulate, specific rotatory powers and NMR spectrumvalues of the compounds obtained in Reference Examples 68 to 76 areshown in Table 11.

                                      TABLE 11    __________________________________________________________________________     ##STR110##    Compound        Specific                            NMR spectrum δ value ppm    No.   R         rotary power                            8-Me(s,3H)                                  3"-OMe(s,3H)                                          others (solvnt)    __________________________________________________________________________    75           ##STR111##                    [α].sub.D.sup.23 -29.2° ( - c 1.0, CH.sub.3                    OH)     1.57  3.35    2.42                                             (NCH.sub.3,s,3H) (CDCl.sub.3)    76    NH.sub.2  [α].sub.D.sup.23 -43.2°                            1.57  3.31       (CDCl.sub.3)                    ( -c 1.0, CHCl.sub.3)    77           ##STR112##                    [α].sub.D.sup.23 -36.4° ( -c 1.0,                    CHCl.sub.3)                            1.56  3.32    2.23                                             (NCH.sub.3,s,3H) (CDCl.sub.3)    78           ##STR113##                    [α].sub.D.sup.23 -34.0° ( -c 1.0,                    CHCl.sub.3)                            1.57  3.36    2.23                                             (NCH.sub.3,s,3H) (CDCl.sub.3)    79           ##STR114##                    [α].sub.D.sup.23 -27.0° ( -c 1.0, CH.sub.3                    OH)     1.58  3.38    3.05                                             (NCH.sub.3,s,3H) (CD.sub.3 OD)    80           ##STR115##                    [α].sub.D.sup.23 -30.8° ( -c 1.0, CH.sub.3                    OH)     1.57  3.36       (CDCl.sub.3)    81           ##STR116##                    [α].sub.D.sup.23 -27.0° ( -c 1.0, CH.sub.3                    OH)     1.58  3.37    2.98                                             (NCH.sub.3,s,3H) (CD.sub.3 OD)    82           ##STR117##                    [α].sub.D.sup.23 -26.4° ( -c 1.0, CH.sub.3                    OH)     1.54  3.34    3.34                                             (NMe.sub.2,s,6H) (CD.sub.3 OD)    83           ##STR118##                    [α].sub.D.sup.23 -25.8° ( -c 1.0, CH.sub.3                    OH)     1.58  3.37    3.19                                             (NMe.sub.2,s,6H) (CD.sub.3    __________________________________________________________________________                                             OD)

REFERENCE EXAMPLE 77

100 mg of 9-dihydroerythromycin A 6,9-epoxide (compound 84) (reference:Japanese Laid-open Patent Publication No. 1588/1972) was dissolved in 1ml of chloroform, then 0.6 ml of methyl iodide was added thereto and themixture was heated under reflux for 1.5 hours. After evaporation of thesolvent, 5 ml of ether was added and the precipitate formed wasfiltered. The precipitate was washed with 10 ml of ether and dried toobtain 85 mg (yield 71%) 9-dihydroerythromycin A 6,9-epoxide methyliodide (compound 85) in white powder.

REFERENCE EXAMPLE 78

100 mg of the compound 84 was dissolved in 1 ml of chloroform, then 0.6ml of ethyl iodide was added thereto and the mixture was heated underreflux for 2 days. After evaporation of the solvent, 5 ml of ether wasadded and the precipitate formed was filtered. The precipitate waswashed with 10 ml of ether and dried to obtain 90 mg (yield 74%) of9-dihydroerythromycin A 6,9-epoxide ethyl iodide (compound 86) in whitepowder.

REFERENCE EXAMPLE 79

100 mg of the compound 84 was dissolved in 1 ml of chloroform, then 0.7ml of propyl iodide was added thereto, and the mixture was heated underreflux for 2 days. After evaporation of the solvent, 5 ml of ether wasadded and the precipitate formed was filtered. The precipitate waswashed with 10 ml of ether and dried to obtain 87 mg (yield 70%) of9-dihydroerythromycin A 6,9-epoxide propyl iodide (compound 87) in whitepowder.

REFERENCE EXAMPLE 80

100 mg of the compound 84 was dissolved in 1 ml of chloroform, then 1.0ml of butyl iodide was added thereto, and the mixture was heated underreflux for 1 days. After evaporation of the solvent, 5 ml of ether wasadded and the precipitate formed was filtered. The precipitate waswashed with 10 ml of ether and dried to obtain 95 mg (yield 76%) of9-dihydroerythromycin A 6,9-epoxide propyl iodide (compound 88) in whitepowder.

The structural formulae, specific rotatory powers and NMR spectrumvalues of the compound obtained in Reference Examples 77 to 80 are shownin Table 12.

                                      TABLE 12    __________________________________________________________________________     ##STR119##    Compound                     NMR spectrum δ value ppm (CD.sub.3                                 OD)    No.    R         [α].sub.D.sup.23 ( -c 1.0, CH.sub.3 OH)                                 3'-NMe(s) 3"-OMe(s,3H)    __________________________________________________________________________    85     CH.sub.3  -38.0°                                  3.29(3'-NMe.sub.3,9H)                                           3.37    86     C.sub.2 H.sub.5                     -35.2°                                 3.19(3'-NMe.sub.2,6H)                                           3.36    87     CH.sub.2 CH.sub.2 CH.sub.3                     -40.6°                                 3.22(3'-NMe.sub.2,6H)                                           3.36    88     CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                     -40.6°                                 3.20(3'-NMe.sub.2,6H)                                           3.36    __________________________________________________________________________

REFERENCE EXAMPLE 81

200 mg of the compound 27 was dissolved in 4 ml of chloroform, then 0.3ml of benzyl chloride was added thereto and the mixture was heated underreflux for 48 hours. Subsequently, the same processing as in ReferenceExample 54 was conducted to obtain 122 mg (yield 52%) of8,9-anhydroerythromycin A 6,9-hemiketal benzyl chloride (compound 89) inwhite powder.

REFERENCE EXAMPLE 82

200 mg of the compound 57 was dissolved in 4 ml of chloroform, then 0.5ml of ethyl iodide was added thereto and the mixture was heated underreflux for 20 hours. Subsequently, the same processing as in ReferenceExample 54 was conducted to obtain 134 mg (yield 56%) of8,9-anhydroerythromycin A 6,9-hemiketal ethyl iodide (compound 90) inpale yellow powder.

REFERENCE EXAMPLE 83

200 mg of the compound 57 was dissolved in 4 ml of chloroform, then 0.5ml of ethyl iodide was added thereto and the mixture was heated underreflux for 20 hours. Subsequently, the same processing as in ReferenceExample 54 was conducted to obtain 126 mg (yield 52%) of11-0-mesyl-8,9-anhydroerythromycin A 6,9-hemiketal ethyl iodide(compound 91) in pale yellow powder.

REFERENCE EXAMPLE 84

200 mg of the compound 27 was dissolved in 4 ml of chloroform, then 0.5ml of ethyl bromide was added thereto and the mixture was heated underreflux for 48 hours. Subsequently, the same processing as in ReferenceExample 54 was conducted to obtain 189 mg (yield 82%) of8,9-anhydroerythromycin A 6,9-hemiketal ethyl bromide (compound 92) inwhite powder.

The structural formulae, specific rotatory powers and NMR spectrumvalues of the compounds obtained in Reference Examples 81-84 are shownin Table 13.

                                      TABLE 13    __________________________________________________________________________     ##STR120##    Compound                        NMR spectrum δ value ppm (CD.sub.3                                    OD)    No.   R.sup.1                R.sup.2                       X [α].sub.D.sup.23 ( -c 1.0, CH.sub.3 OH)                                    8-Me(s,3H)                                          3-NMe.sub.2 (s,6H)                                                 3"-OMe(s,3H)                                                         others    __________________________________________________________________________    89    H     CH.sub.2 Ph                       Cl                         -39.6°                                    1.59  3.09   3.34    7.54 (Ph, broad                                                         s,5H)    90    SO.sub.2 CH.sub.3                C.sub.2 H.sub.5                       I -26.4°                                    1.60  3.17   3.37    3.24 (SO.sub.2                                                         CH.sub.3,s,3H)    91    SO.sub.2 CH.sub.3                CH.sub.2 CH.sub.2 CH.sub.3                       I -27.8°                                    1.60  3.18   3.37    3.24 (SO.sub.2                                                         CH.sub.3,s,3H)    92    H     C.sub.2 H.sub.5                       Br                         -31.2°                                    1.59  3.19   3.38    __________________________________________________________________________

REFERENCE EXAMPLE 85

By use of 68 mg of anhydroerythromycin A (compound 93) [reference: P.Kurath, et al., Experientia, 27, 362 (1971)] and 0.2 ml of ethyl iodide,the same processing as Reference Example 54 was conducted to obtain 69mg of anhydroerythromycin A ethyl iodide (compound 94) in white powder(yield 75%).

REFERENCE EXAMPLE 86

By use of 105 mg of the compound (93) and 0.3 ml of propyl iodide, thesame processing as Reference Example 55 was conducted to obtain 93 mg ofanhydroerythromycin A propyl iodide (compound 95) in pale yellow powder(yield 72%).

REFERENCE EXAMPLE 87

By use of 105 mg of the compound (93) and 0.5 ml of benzyl chloride, thesame processing as Reference Example 55 was conducted to obtainanhydroerythromycin A benzyl chloride (compound 96) in a yield of 75%.

The structural formulae, specific rotatory powers and NMR of thecompounds obtained in Reference Examples 85 to 87 shown in Table 14.

                                      TABLE 14    __________________________________________________________________________     ##STR121##    compound       specific NMR spectrum δ value ppm (CD.sub.3 OD)    No.    R    X  rotary power                            3"-OMe,S,3H                                    3'-NMe.sub.2,S,6H                                            others    __________________________________________________________________________    94     C.sub.2 H.sub.5                I  [α]  -35.8°                            3.25    3.39                   ( -c 1.0, CH.sub.3 OH)    95     C.sub.3 H.sub.7                I  [α] -34.0°                            3.29    3.29                   ( -c 1.0, CH.sub.3 OH)    96     CH.sub.2 Ph                Cl [α] -18.6°                            3.32    3.10    7.57                   ( -c 1.0, CH.sub.3 OH)   (Ph,m,5H)    __________________________________________________________________________

REFERENCE EXAMPLE 88

206 mg of the compound 76 was dissolved in 3 ml of methanol, then 76 mgof sodium hydrogen carbonate and 0.5 ml of ethyl iodide were addedthereto, and the mixture was stirred at 50° C. overnight. This reactionmixture was diluted with 30 ml of ethyl acetate, and washed with asaturated aqueous sodium hydrogen carbonate and saturated aqueous sodiumchloride solution. The ethyl acetate solution was dried over anhydroussodium sulfate and the solvent was evaporated under reduced pressure.The residue was purified by silica gel column chromatography (developingsolvent: chloroform-methanol-conc. aqueous ammonia (50:1: 0.1)) toobtain 98 mg (yield 44%) of diethyl-dinor-8,9-anhydroerythromycin A6,9-hemiketal (compound 98).

REFERENCE EXAMPLE 89

By using 550 mg of the compound 76, 1-6 ml of 1,5-dibromopentane and 202mg of sodium hydrogen carbonate, the same processing as in ReferenceExample 73 was conducted to obtain 327 mg (yield 54%) of de(dimethylamino)-3'-piperidyl-8,9-anhydroerythromycin A 6,9-hemiketal(compound 99) in white powder.

REFERENCE EXAMPLE 90

By using 78 mg of the compound 97 and 1 ml of ethyl iodide, the sameprocessing as in Reference Example 72 was conducted to obtain 15 mg(yield 16%) of diethyl-dinor-8,9-anhydroerythromycin A 6,9-hemiketalethyl iodide (compound 100) in pale yellow powder.

REFERENCE EXAMPLE 91

By using 93 mg of the compound 80 and 1 ml of ethyl iodide, the sameprocessing as in Reference Example 72 was conducted to obtain 94 mg(yield 84%) of de(dimethylamino)-3'-pyrrolidino-8,9-anhydroerythromycinA 6,9-hemiketal ethyl iodide (compound 101) in pale yellow powder.

REFERENCE EXAMPLE 92

83 mg of the compound 99 and 0.5 ml of methyl iodide were dissolved in0.5 ml of chloroform, and stirred at 40° C. for 9 hours. Thereafter, thesame processing as in Example 50 was conducted to obtain 84 mg (yield85%) of de(dimethylamino)-3'-piperidino-8,9-anhydroerythromycin A6,9-hemiketal methyl iodide (compound 102) in pale yellow powder.

REFERENCE EXAMPLE 93

By using 94 mg of the compound 99 and 1 ml of ethyl iodide, the sameprocessing as in Reference Example 72 was conducted to obtain 33 mg(yield 29%) of de(dimethylamino)-3'-piperidino-8,9-anhydroerythromycin A6,9-hemiketal ethyl iodide (compound 103) in pale yellow powder.

REFERENCE EXAMPLE 94

By using 50 mg of the compound 27 and 0.6 ml of propargyl bromide, thesame processing as in Reference Example 50 was conducted to obtain 52 mg(yield 89%) of 8,9-anhydroerythromycin A 6,9-hemiketal propargyl bromide(compound 104) in white powder.

REFERENCE EXAMPLE 95

By using 111 mg of the compound 32 and 0.12 ml of propargyl bromide, thesame processing as in Reference Example 50 was conducted to obtain 111mg (yield 87 %) of 11,12-di-0-acetyl-8,9-anhydroerythromycin A6,9-hemiketal propargyl bromide (compound 105) in white powder.

The structural formula, specific rotatory powers and NMR spectrum valuesof the compounds obtained in Reference Examples 88-95 are shown in Table15.

                                      TABLE 15    __________________________________________________________________________     ##STR122##    Compound                 Specific NMR spectrum δ value ppm    No.    R     X           rotary power                                      8-Me(s,3H)                                             3"-OMe(s,3H)                                                      others    __________________________________________________________________________                                                      (solvent)     97    H     N(C.sub.2 H.sub.5).sub.2                             [α].sub.D.sup.22 -27.2°                                      1.56   3.36        (CDCl.sub.3)                             (  -c 1.0, CHCl.sub.3)     98    H                  ##STR123## [α].sub.D.sup.22 -34.8° ( -c 1.0,                             CHCl.sub.3)                                      1.56   3.35        (CDCl.sub.3)     99    H                  ##STR124## [α].sub.D.sup.22 -33.8° ( -c 1.0,                             CHCl.sub.3)                                      1.56   3.35        (CDCl.sub.3)    100    H     N.sup.⊕ (C.sub.2 H.sub.5).sub.3.I.sup.⊖                             [α].sub.D.sup.22 -24.2°                                      1.59   3.37     (CD.sub.3 OD)                             ( -c 1.0, CH.sub.3 OH)                                      1.59   3.37        (CD.sub.3 OD)    101    H                  ##STR125## [α].sub.D.sup.22 -27.0° ( -c 1.0,                             CH.sub.3 OH)                                      1.59   3.35        (CD.sub.3 OD)    102    H                  ##STR126## [α].sub.D.sup.22 -27.0° ( -c 1.0,                             CH.sub.3 OH)                                      1.58   3.38     3.13                                                         (3'-NMe,s,3H)                                                         (CD.sub.3 OD)    103    H                  ##STR127## [α].sub.D.sup.22 -26.6° ( -c 1.0,                             CH.sub.3 OH)                                      1.57   3.36        (CD.sub.3 OD)    104    H                  ##STR128## [α].sub.D.sup.22 -31.0° ( -c 1.0,                             CH.sub.3 OH)                                      1.58   3.39     3.26                                                         (3'-NMe.sub.2,s,6H)                                                         (CD.sub.3 OD)    105    COCH.sub.3                  ##STR129## [α].sub.D.sup. 22 -20.0° ( -c 1.0,                             CH.sub.3 OH)                                      1.51   3.39     2.01 2.04 3.27                                                         (11-COCH.sub.3,s,3H)                                                         12-COCH.sub.3,s,3H)                                                         (3'-NMe.sub.2,s,6H)                                                         (CD.sub.3 OD)    __________________________________________________________________________

REFERENCE EXAMPLE 96

120 mg of 11-0-methylerythromycin A (reference: Japanese Laid-openPatent Publication No. 192294/1982) was dissolved in 6 ml of glacialacetic acid and the solution was stirred for one and a half hours. Thereaction mixture was poured into 15 ml of ice-cooled conc. aqueousammonia. This mixture was extracted 3 times with 10 ml of chloroform.This chloroform solution was dried over anhydrous sodium sulfate, andthe solvent was evaporated under reduced pressure. The residue waspurified by silica gel chromatography (developingsolvent:chloroform-methanol-conc. aqueous ammonia (20:1:0.01)) to obtain95 mg (yield 75%) of 11-0-methyl-8,9-anhydroerythromycin A 6,9-hemiketal(compound 106) in white powder.

REFERENCE EXAMPLE 97

125 mg of 11-0-ethylerythromycin A (reference: Japanese Laid-open PatentPublication No. 192294/1982) was treated in the same manner as inReference Example 96 to obtain 102 mg (yield 84%) of11-0-ethyl-8,9-anhydroerythromycin A 6,9-hemiketal (compound 107) inwhite powder.

REFERENCE EXAMPLE 98

120 mg of the compound 48 was dissolved in 3.2 ml of chloroform, thenadded with 2 mg of 4-dimethyl aminopyridine, 0.86 ml of triethylamineand 0.86 ml of propionic anhydride, and heated under reflux for 3 days.The reaction mixture was cooled to room temperature and the same processas that for obtaining the compound 28 was conducted to obtain a paleyellow glass-like substance. This substance was dissolved, withoutpurification, in 6 ml of methanol, and heated under reflux for 3 days.The solution was cooled to room temperature and concentrated underreduced pressure to obtain a pale yellow glass-like substance. Thissubstance was purified by silica gel column chromatography, utilizing adeveloping solvent system of chloroform-methanol-conc. aqueousammonia=50:1:0.01, to obtain 65 mg (yield 55%) of11-0-propionyl-12-0-acetyl-8,9-anhydroerythromycin A 6,9-hemiketal(compound 108) in white powder.

Rf value: 0.16 (chloroform:methanol:conc. aqueous ammonia=10:1:0.01),low mass: M+813, high mass: 813.486 (calcd, for C₄₂ H₇₁ NO₁₄ : 813.487)

REFERENCE EXAMPLE 99

120 mg of the compound 48 was dissolved in 3.2 ml of chloroform, thenadded with 2 mg of 4-dimethylaminopyridine, 0.86 ml of triethylamine and0.86 ml of butyric anhydride, and processed in the same manner as in thepreparation of the compound 108 to obtain 75 mg (yield 63%) of11-0-butyryl-12-0-acetyl-8,9-anhyroery- thromycin A 6,9-hemiketal(compound 109) in white powder.

Rf value: 0.16 (chloroform-methanol-conc. aqueous ammonia=10:1:0.01),low mass: M+827, high mass: 827.502 (calcd. for C₄₃ H₇₃ NO₁₄ :827.502).

REFERENCE EXAMPLE 100

100 mg of the compound 32 was dissolved in 1 ml of chloroform and heatedunder rellux for 2 days with addition of 0.5 ml of ethyl bromide.Thereafter, the same processing as in Reference Example 50 was conductedto obtain 98 mg (yield 86%) of11,12-di-0-acetryl-8,9-anhydroerythromycin A 6,9-hemiketal ethyl,bromide (compound 110) in white powder.

REFERENCE EXAMPLE 101

150 mg of the compound 27 was dissolved in 1 ml of chloroform, them 1 mlof bromoacetate and 0.5 ml of diisopropylethylamine were added theretoand the mixture was stirred for 6 hours. After evaporation of thesolvent, 5 ml of ether was added and the precipitate formed wasfiltered. The precipitate was washed with 10 ml of ether and dried toobtain 145 mg (yield 80 %) of 8,9- anhydroerythromycin A 6,9-hemiketalmethoxycarbonyl methyl bromide (compound 111) in white powder.

REFERENCE EXAMPLE 102

150 mg of the compound 27 was dissolved in 1 ml of chloroform, then 200mg of bromoacetic acid and 0.5 ml of diisopropylethylamine were addedthereto and the mixture was heated under reflux for 6 hours. Afterevaporation of the solvent 5 ml of ether was added and the precipitateformed was filtered. The precipitate was washed with 10 ml of ether anddried to obtain 127 mg (yield 71%) of 8,9-anhydroerythromycin A6,9-hemiketal carboxymethyl bromide (compound 112) in white powder.

REFERENCE EXAMPLE 103

150 mg of the compound 27 was dissolved in 1 ml of chloroform, then 0.5ml of monofluoroethyl bromide was added thereto and the mixture washeated under reflux for 5 days. Subsequently, the same processing as inReference Example 75 was conducted to obtain 135 mg (yield 76%) of8,9-anhydroerythromycin A 6,9-hemiketal 2-fluoroethyl bromide (compound13) in white powder.

REFERENCE EXAMPLE 104

150 mg of the compound 27 was dissolved in 1 ml of chloroform, then 0.5ml of bromoacetonitrile was added thereto and the mixture was allowed tostand at room temperature for 5 hours. Subsequently, the same processingas in Reference Example 75 was conducted to obtain 165 mg (yield 94 %)of 8,9-anhydroerythromycin A 6,9-hemiketal cyanomethyl bromide (compound114) in white powder.

The structural formulae, specific rotatory powers and NMR spectrumvalues of the compounds obtained in Reference Examples 96-104 are shownin Table 16.

                                      TABLE 16    __________________________________________________________________________     ##STR130##    Com-                     Specific    pound                    rotary NMR spectrum δ value ppm    No. R.sup.1             R.sup.2                  X          power  8-Me(s,3H)                                          3'-NMe.sub.2 (s,6H)                                                  3'-OMe(s,3H)                                                         others    __________________________________________________________________________                                                         (solvent)    106 CH.sub.3             H    N(CH.sub.3).sub.2                             [α].sub.D.sup.24 -39.6°                                     1.56 2.29    3.36   11-OMe 3.49 (s,3H)                             ( -c 1.0,CHCl.sub.3)        (CDCl.sub.3)    107 C.sub.2 H.sub.5             H    N(CH.sub.3).sub.2                             [α].sub.D.sup.24 -29.8°                                     1.56 2.30    3.36   (CDCl.sub.3)                             ( -c 1.0,CHCl.sub.3)    108 COC.sub.2 H.sub.5             COCH.sub.3                  N(CH.sub.3).sub.2                             [α].sub.D.sup.24 -20.2°                                     1.61 2.33    3.34   12-OAc 2.03 (s,3H)                             ( -c 1.0,CHCl.sub.3)        (CDCl.sub.3)    109 COC.sub.3 H.sub.7             COCH.sub.3                  N(CH.sub.3).sub.2                             [α].sub.D.sup.24 -18.2°                                     1.58 2.29    3.32   12-OAc 2.00 (s,3H)                             ( -c 1.0,CHCl.sub.3)        (CDCl.sub.3)    110 COCH.sub.3             COCH.sub.3                   ##STR131##                             [α].sub.D.sup.22 -26.4° ( -c                             1.0,CH.sub.3 OH)                                     1.60 3.17    3.38   11-OAc 2.01 (s,3H)                                                         12-OAc                                                         2.05 (CD.sub.3 OD)    111 H    H                   ##STR132##                             [α].sub.D.sup.22 -30.0° ( -c                             1.0,CH.sub.3 OH)                                     1.56 3.35    3.37   (CD.sub.3 OD)    112 H    H                   ##STR133##                             [α].sub.D.sup.22 -31.8° ( -c                             1.0,CH.sub.3 OH)                                     1.58 3.38    3.38   (CD.sub.3 OD)    113 H    H                   ##STR134##                             [α].sub.D.sup.22 -26.0° ( -c                             1.0,CH.sub.3 OH)                                     1.59 3.35    3.38   (CD.sub.3 OD)    114 H    H                   ##STR135##                             [α].sub.D.sup.22 -40.4° ( -c                             1.0,CH.sub.3 OH)                                     1.58 3.35    3.38   (CD.sub.3 OD)    __________________________________________________________________________

REFERENCE EXAMPLE 105

By using 200 mg of 9-dihydroerythromycin A 6,9-epoxide (compound 84)(reference : Japanese Laid-open Patent Publication No. 1588/1972) and0.5 ml of allyl bromide, the same processing as in Reference Example 50was conducted to obtain 190 mg of 9-dihydroerythromycin A 6,9-epoxideallyl bromide (compound 115 in white powder.

REFERENCE EXAMPLE 106

By using 200 mg of 9-dihydroerythromycin A 6,9-epoxide (compound 84) and0.5 ml of propargyl bromide, the same processing as in Reference Example50 was conducted to obtain 195 mg (yield 84%) of 9-dihydroerythromycin A6,9-epoxide propargyl bromide (compound 116) in white powder.

The structural formulae, specific rotatory powers and NMR spectrumvalues of the compounds obtained in Reference Examples 105 and 106 areshown in Table 17.

                                      TABLE 17    __________________________________________________________________________     ##STR136##    Compound                 NMR spectrum δ value ppm (CD.sub.3 OD)    No.   R       [α].sub.D.sup.22 ( -c 1.0, CH.sub.3 OH)                             3'-NMe(s,6H)                                      3"-OMe(s,3H)    __________________________________________________________________________    115   CH.sub.2 CHCH.sub.2                  -38.4°                             3.16     3.36    116   CH.sub.2 CCH                  -41.2°                             3.20     3.37    __________________________________________________________________________

REFERENCE EXAMPLE 107

505 mg of the compound 75 was dissolved in 5 ml of methanol, then 121 mgof sodium hydrogen carbonate and 68.5 μl of allyl bromide were addedthereto, and the mixture was stirred at 50° C. for two hours. Thisreaction mixture was diluted with 35 ml of ethyl acetate, and thesolution was washed with a saturated aqueous sodium hydrogen carbonateand a saturated aqueous sodium chloride solution. The ethyl acetatesolution was dried over anhydrous sodium sulfate and the solvent wasevaporated under reduced pressure. The residue was purified by silicagel column chromatography (eluant: chloroform- methanol-conc. aqueousammonia (10:1:0.1)) to obtain 72 mg (yield 67%) ofallyl-nor-8,9-anhydroerythromycin A 6,9-hemiketal (compound 117) inwhite powder.

REFERENCE EXAMPLE 108

By using 105 mg of the compound 75, 25 mg of sodium hydrogen carbonateand 14.7 μl of propargyl bromide, the same processing as in ReferenceExample 107 was conducted to obtain 66 mg (yield 60%) ofpropargyl-nor-8,9-anhydroerythromycin A 6,9-hemiketal (compound 118) inwhite powder.

REFERENCE EXAMPLE 109

105 mg of the compound 75 was dispersed in 1 ml of methanol, then 0.29ml of diisopropylethylamine and 0.29 ml of 1-iodopropane were addedthereto, and the mixture was stirred at 50° C. for 22 hours. Thisreaction mixture was diluted with 20 ml of ethyl acetate, and thesolution was washed with a saturated aqueous sodium hydrogen carbonateand a saturated aqueous sodium chloride solution. The ethyl acetatesolution was dried over anhydrous sodium sulfate and the solvent wasevaporated under reduced pressure. The residue was purified by silicagel column chromatography (eluant: chloroform-methanol-conc. aqueousammonia (50:1: 0.1)) to obtain 84 mg (yield 75%) ofpropyl-nor-8,9-anhydroerythromycin A 6,9-hemiketal (compound 119) inwhite powder.

REFERENCE EXAMPLE 110

By using 105 mg of the compound 75, 0.26 ml of diisopropylethylamine and0.21 ml of bromoethanol, the same processing as in Reference Example 109was conducted to obtain 94 mg (yield 84%) of2-hydroxyethyl-nor-8,9-anhydroerythromycin A 6,9-hemiketal (compound120) in white powder.

REFERENCE EXAMPLE 111

By using 351 mg of the compound 75, 0.87 ml of diisopropylethylamine and2 ml of 2-iodopropane, the same processing as in Reference Example 109was conducted to obtain 101 mg (yield 27%) ofisopropyl-nor-8,9-anhydroerythromycin A 6,9-hemiketal (compound 121) inwhite powder.

REFERENCE EXAMPLE 112

By using 351 mg of the compound 75, 0.87 ml of diisopropylethylamine and2.2 ml of isobutyl bromide, the same processing as in Reference Example109 was conducted to obtain 52 mg (yield 14%) ofisobutyl-nor-8,9-anhydroerythromycin A 6,9-hemiketal (compound 122) inwhite powder.

REFERENCE EXAMPLE 113

1.0 g of the compound 76 was dispersed in 10 ml of methanol, to this 2.5ml of diisopropylethylamine and 1.3 ml of allyl bromide were added, andthe mixture was stirred at 50° C. for 40 minutes. The solvent wasremoved under reduced pressure, and the residue was purified by silicagel column chromatography (eluant: chloroform- methanol-conc. aqueousammonia (50:1:0.1)) to obtain 337 mg (yield 30%) ofdiallyl-dinor-8,9-anhydroerythromycin A 6,9-hemiketal (compound 123) inwhite powder and 256 mg (yield 24%) ofallyl-dinor-8,9-anhydroerythromycin A 6,9-hemiketal (compound 124) inwhite powder.

REFERENCE EXAMPLE 114

500 mg of the compound 76 was dispersed in 5 ml of methanol, to thiswere added 0.64 ml of diisopropylethylamine and 0.33 ml of propargylbromide, and the mixture was stirred at 50° C. for 1 hour. The solventwas removed under reduced pressure, and the residue was purified bysilica gel column chromatography (eluant: chloroform-methanol-conc.aqueous ammonia (100:1:0.1)) to obtain 114 mg (yield 21%) ofdipropargyl-dinor-8,9-anhydroerythromycin A 6,9-hemiketal (compound 125)in white powder and 252 mg (yield 45%) of propargyl-dinor-8,9-anhydroerythromycin A 6,9-hemiketal (compound 126) in white powder.

REFERENCE EXAMPLE 115

By using 256 mg of the compound 124, 0.61 ml of diisopropylethylamineand 0.31 ml of propargyl bromide, the same processing as in ReferenceExample 109 was conducted to obtain 207 mg (yield 77%) ofN-allyl-N-propargyl-dinor-8,9-anhydroerythromycin A 6,9-hemiketal(compound 127) in white powder.

REFERENCE EXAMPLE 116

By using 100 mg of the compound 117 and 0.1 ml of allyl bromide, thesame processing as in Reference Example 50 was conducted to obtain 110mg (yield 94%) of allyl-nor-8,9- anhydroerythromycin A 6,9-hemiketalallyl bromide (compound 128) in white powder.

REFERENCE EXAMPLE 117

By using 100 mg of the compound 117 and 0.1 ml of propargyl bromide, thesame processing as in Reference Example 50 was conducted to obtain 102mg (yield 85%) of allyl-nor-8,9-anhydroerythromycin A 6,9-hemiketalpropargyl bromide (compound 129) in white powder.

REFERENCE EXAMPLE 118

By using 61 mg of the compound 118 and 0.1 ml of propargyl bromide, thesame processing as in Reference Example 50 was conducted to obtain 51 mg(yield 72%) of propargyl-nor-8,9-anhydroerythromycin A 6,9-hemiketalpropargyl bromide (compound 130) in white powder.

REFERENCE EXAMPLE 119

By using 99 mg of the compound 123 and 0.1 ml of allyl bromide, the sameprocessing as in Reference Example 50 was conducted to obtain 16 mg(yield 14%) of diallyl-dinor-8,9-anhydroerythromycin A 6,9-hemiketalallyl bromide (compound 131) in white powder.

REFERENCE EXAMPLE 120

61 mg of the compound 123 was dissolved 1 ml of methanol, then 12 mg ofsodium hydrogen carbonate and 81.9 μl of propargyl bromide were addedthereto, and the mixture thereof was stirred at room temperature for 3days. The same processing as in Reference Example 50 was hereinafterconducted to obtain 32 mg (yield 39%) ofdiallyl-dinor-8,9-anhydroerythromycin A 6,9-hemiketal propargyl bromide(compound 132) in white powder.

REFERENCE EXAMPLE 121

By using 101 mg of the compound 126, 24 mg of sodium hydrogen carbonateand 0.1 ml of propargyl bromide, the same processing as in ReferenceExample 120 was conducted to obtain 38 mg (yield 30%) ofdipropargyl-dinor-8,9-anhydroerythromycin A 6,9-hemiketal propargylbromide (compound 133) in white powder.

REFERENCE EXAMPLE 122

By using 50 mg of the compound 121, and 0.1 ml of iodomethane, the sameprocessing as in Reference Example 50 was conducted to obtain 52 mg(yield 86%) of 8,9-anhydroerythromycin A 6,9-hemiketal isopropyl iodide(compound 134) in white powder.

REFERENCE EXAMPLE 123

By using 29 mg of the compound 122, and 0.4 ml of iodomethane, the sameprocessing as in Reference Example 50 was conducted to obtain 30 mg(yield 86%) of 8,9-anhydroerythromycin A 6,9-hemiketal isopropyl iodide(compound 135) in white powder.

REFERENCE EXAMPLE 124

150 mg of the compound 27 was dissolved in 3 ml of chloroform, then 1 mlof butyl iodide was added thereto and the mixture was heated underreflux for 3 days. The same processing as in Reference Example 50 washereinafter conducted to obtain 121 mg (yield 64%) of8,9-anhydroerythromycin A 6,9 hemiketal butyl iodide (compound 136) inwhite powder.

REFERENCE EXAMPLE 125

150 mg of the compound 27 was dissolved in 2 ml of chloroform, then 0.3ml of cyclopropylmethyl bromide was added thereto and the mixture washeated under reflux for 2 days. The same processing as in ReferenceExample 50 was hereinafter conducted to obtain 145 mg (yield 81%) of8,9-anhydroerythromycin A 6,9 hemiketal cyclopropyl-methyl bromide(compound 137) in white powder.

REFERENCE EXAMPLE 126

150 mg of the compound 27 was dissolved in 2 ml of chloroform, then 0.5ml of crotyl bromide was added thereto and the mixture was allowed tostand at room temperature for 6 hours. The same processing as inReference Example 50 was hereinafter conducted to obtain 175 mg (yield98%) of 8,9-anhydroerythromycin A 6,9-hemiketal crotyl bromide (compound138) in white powder.

REFERENCE EXAMPLE 127

150 mg of the compound 27 was dissolved in 1.5 ml of chloroform, then0.5 ml of 2,3-dibromopropene was added thereto and the mixture wasallowed to stand at room temperature for 1 day. The same processing asin Reference Example 50 was hereinafter conducted to obtain 111 mg(yield 58%) of 8,9-anhydroerythromycin A 6,9-hemiketal 2-bromoallylbromide (compound 139) in white powder.

REFERENCE EXAMPLE 128

150 mg of the compound 27 was dissolved in 3 ml of chloroform, then 0.5ml of propargyl chloride was added thereto and the mixture thereof washeated under reflux for 1 day. The same processing as in ReferenceExample 50 was conducted to obtain 156 mg (yield 94%) of8,9-anhydroerythromycin A 6,9-hemiketal propargyl chloride (compound140) in white powder.

The structural formulae, specific rotatory powers and NMR spectrumvalues of the compounds obtained in Reference Examples 108-129 are shownin Table 18.

                                      TABLE 18    __________________________________________________________________________     ##STR137##    Compound                       NMR spectrum δ value ppm    No.    R              [α].sub.D.sup.24 ( -c 1.0)                                   8-Me(s,3H)                                          3"-OMe(s,3H)                                                   Others (solvent)    __________________________________________________________________________    117            ##STR138##    -40.2° (CHCl.sub.3)                                   1.56   3.33     2.19 (3'-NMe,s,3H)                                                   (CDCl.sub.3)    118            ##STR139##    -40.2° (CHCl.sub.3)                                   1.57   3.36     2.35 (3'-NMe,s,3H)                                                   (CDCl.sub.3)    119            ##STR140##    -36.2° (CHCl.sub.3)                                   1.57   3.36     2.23 (3'-NMe,s,3H)                                                   (CDCl.sub.3)    120            ##STR141##    -32.4° (CHCl.sub.3)                                   1.57   3.35     2.34 (3'-NMe,s,3H)                                                   (CDCl.sub.3)    121            ##STR142##    -36.8° (CHCl.sub.3)                                   1.56   3.36     2.21 (3'-NMe,s,3H)                                                   (CDCl.sub.3)    122            ##STR143##    -36.6° (CHCl.sub.3)                                   1.57   3.36     2.22 (3'-NMe,s,3H)                                                   (CDCl.sub.3)    123    N(CH.sub.2 CHCH.sub.2).sub.2                          -39.6° (CHCl.sub.3)                                   1.56   3.32     (CDCl.sub.3)    124            ##STR144##    -31.4° (CHCl.sub.3)                                   1.57   3.35     (CDCl.sub.3)    125    N(CH.sub.2 CCH).sub.2                          -28.4° (CHCl.sub.3)                                   1.57   3.36     (CDCl.sub.3)    126            ##STR145##    -32.2° (CHCl.sub.3)                                   1.57   3.36     (CDCl.sub.3)    127            ##STR146##    -31.2° (CHCl.sub.3)                                   1.57   3.36     (CDCl.sub.3)    128            ##STR147##    -24.4° (CH.sub.3 OH)                                   1.59   3.36     3.07 (3'-NMe,s,3H)                                                   (CD.sub.3 OD)    129            ##STR148##    -23.8° (CH.sub.3 OH)                                   1.59   3.39     3.17 (3'-NMe,s,3H)                                                   (CD.sub.3 OD)    130            ##STR149##    -20.5° (CH.sub.3 OH)                                   1.59   3.40     3.29 (3'-NMe,s,3H)                                                   (CD.sub.3 OD)    131    .sup.⊕ N(CH.sub.2 CHCH.sub.2).sub.3 Br.sup.⊖                          -13.3° (CH.sub.3 OH)                                   1.58   3.34     (CD.sub.3 OD)    132            ##STR150##    -18.0° (CH.sub.3 OH)                                   1.59   3.36     (CD.sub.3 OD)    133    .sup.⊕ N(CH.sub.2 CCH).sub.3 Br.sup.⊖                          -18.4° (CH.sub.3 OH)                                   1.58   3.39     (CD.sub.3 OD)    134            ##STR151##    -26.4° (CH.sub.3 OH)                                   1.58   3.36     2.90 (3'-NMe.sub.2,s,6H)                                                   (CD.sub.3 OD)    135            ##STR152##    -26.0° (CH.sub.3 OH)                                   1.59   3.38     3.19 (3'-NMe.sub.2,s,6H)                                                   (CD.sub.3 OD)    136            ##STR153##    -29.4° (CH.sub.3 OH)                                   1.59   3.39     3.22 (3'-NMe.sub.2,s,6H)                                                   (CD.sub.3 OD)    137            ##STR154##    -24.4° (CH.sub.3 OH)                                   1.58   3.37     3.24 (3'-NMe.sub.2,s,6H)                                                   (CD.sub.3 OD)    138            ##STR155##    -29.6° (CH.sub.3 OH)                                   1.58   3.38     3.13 (3'-NMe.sub.2,s,6H)                                                   (CD.sub.3 OD)    139            ##STR156##    -26.2° (CH.sub.3 OH)                                   1.58   3.34     3.34 (3'-NMe.sub.2,s,6H)                                                   (CD.sub.3 OD)    140            ##STR157##    -27.8° (CH.sub.3 OH)                                   1.58   3.39     3.26 (3'-NMe.sub.2,s,6H)                                                   (CD.sub.3 OD)    __________________________________________________________________________

REFERENCE EXAMPLE 129

73.5 mg of the compound 32 was dissolved in 0.8 ml of methanol, and 0.2ml of water was added thereto, followed by addition of 66.4 mg of CH₃COONa·3H₂ O. The reaction mixture was heated at 50° C., and stirredafter 26 mg of iodine was added thereto. In order to maintain the pH ofthe reaction mixture at 8 to 9, 0.4 ml portions of 1N aqueous sodiumhydroxide solution were added thereto after 10 minutes, 30 minutes and 1hour, respectively, and the stirring was further continued for 1 hour.The solution was thereafter poured into 100 ml of dilute aqueous ammoniaand the resultant product was extracted with chloroform. The extract waswashed with dilute aqueous ammonia and dried with anhydrous sodiumsulfate. Thereafter, the solvent was distilled off under reducedpressure. The residue was purified by silica gel column chromatography[eluant: chloroform-methanol-conc. aqueous ammonia (15:1:0.1)] to obtain51 mg (yield 70 %) of 11,12-di-0-acetyl-de-N-methyl-8,9-anhydroerythromycin A 6,9-hemiketal (compound 141) in white powder.

REFERENCE EXAMPLE 130

By using 79 mg of the compound 141, 0.17 ml of diisopropylethylamine and0.16 ml of iodomethane, the same processing as in Reference Example 109was conducted to obtain 30 mg (yield 37%) of11,12-di-0-acetyl-N-ethyl-nor-8,9-anhydroerythromycin A 6,9-hemiketal(compound 142) in white powder.

REFERENCE EXAMPLE 131

By using 500 mg of the compound 20, 468 mg of CH₃ COONa·3H₂ O and 170 mgof iodine, the same processing as in Reference Example 129 was conductedto obtain 413 mg (yield 84%) of de-N-methyl-8,9-anhydroerythromycin A6,9-hemiketal cyclic 11,12-carbonate (compound 143) in white powder.

REFERENCE EXAMPLE 132

By using 350 mg of the compound 143, 0.84 ml of diisopropylethylamineand 0.77 ml of iodoethane, the same processing as in Reference Example109 was conducted to obtain 254 mg (yield 69%) ofN-ethyl-nor-8,9-anhydroerythromycin A 6,9-hemiketal cyclic 11,12carbonate(compound 144) in white powder.

REFERENCE EXAMPLE 133

By using 24.8 mg of 8,9-anhydroerythromycin B 6,9-hemiketal (reference:P. Kurath, et al., Experientia, 27, 362,1971) and 0.2 ml of bromoethane,the same processing as in Reference Example 100 was conducted to obtain20 mg (yield 69%) of 8,9-anhydroerythromycin B 6,9-hemiketal ethylbromide (compound 145) in white powder.

REFERENCE EXAMPLE 134

By using 24.7 mg of 8,9-anhydroerythromycin B 6,9-hemiketal and 0.05 mlof propargyl bromide, the same processing as in Reference Example 50 wasconducted to obtain 24 mg (yield 83%) of 8,9-anhydroerythromycin B6,9-hemiketal propargyl bromide (compound 146) in white powder.

REFERENCE EXAMPLE 135

By using 50 mg of the compound 54 and 0.3 ml of propargyl bromide, thesame processing as in Reference Example 50 was conducted to obtain 54 mg(yield 93%) of 11,12-0-isopropylidene-8,9-anhydroerythromycin A6,9-hemiketal propargyl bromide (compound 147) in white powder.

REFERENCE EXAMPLE 136

By using 50 mg of the compound 39 and 0.3 ml of propargyl bromide, thesame processing as in Reference Example 50 was conducted to obtain 55 mg(yield 96%) of 8,9-anhydroerythromycin A 6,9-hemiketal11,12-phenylboronate propargyl bromide (compound 148) in white powder.

REFERENCE EXAMPLE 137

By using 100 mg of the compound 20 and 0.3 ml of propargyl bromide, thesame processing as in Reference Example 50 was conducted to obtain 108mg (yield 93%) of 8,9-anhydroerythromycin A 6,9-hemiketal11,12-cyclic-carbonate propargyl bromide (compound 149) in white powder.

REFERENCE EXAMPLE 138

By using 100 mg of the compound 37 and 0.3 ml of propargyl bromide, thesame processing as in Reference Example 50 was conducted to obtain 107mg (yield 93%) of 8,9-anhydroerythromycin A 6,9-hemiketal 11,12-sulfitepropargyl bromide (compound 150) in white powder.

REFERENCE EXAMPLE 139

100 mg of the compound 8 was dissolved in 2 ml of dry dimethylsulfoxide, and to this, were added 1 ml of acetic anhydride and 0.3 mlof aceticacid. The reaction mixture was allowed to stand for 1 day atroom temperature. Thereafter, the same processing as in ReferenceExample 39 was conducted to obtain 65 mg (yield 56%) of2'-0-acetyl-4"-0-formyl-11,12-di-0-methylthiomethyl-8,9-anhydroerythromycinA 6,9-hemiketal (compound 151) in white powder.

REFERENCE EXAMPLE 140

150 mg of the compound 151 was dissolved in 6 ml of methanol, and tothis, was added 1 ml of conc. aqueous ammonia. The reaction mixture washeated, for 2 days under reflux. Thereafter, the same processing as inReference Example 40 was conducted to obtain 105 mg (yield 76%) of11,12-di-0-methylthiomethyl-8,9-anhydroerythromycin A 6,9-hemiketal(compound 152) in white powder.

REFERENCE EXAMPLE 141

By using 100 mg of the compound 152 and 0.2 ml of propargyl bromide, thesame processing as in Reference Example 50 was conducted to obtain 98 mg(yield 86%) of 11,12-di-0-methylthiomethyl-8,9-anhydroerythromycin A6,9-hemiketal propargyl bromide (compound 153) in white powder.

REFERENCE EXAMPLE 142

99 mg of the compound 1 was dissolved in 3 ml of chloroform, then 0.5 mlof propargyl bromide was added thereto and the mixture was allowed tostand at room temperature for 3 hours. The same processing as inReference Example 50 was hereinafter conducted to obtain 76 mg (yield66%) of 2'-0-acetyl-8,9-anhydroerythromycin A 6,9-hemiketal (compound154) in white powder.

The structural formulae, specific rotatory powers and NMR spectrumvalues of the compounds obtained in Reference Examples 129-142 are shownin Table 19.

                                      TABLE 19(a)    __________________________________________________________________________     ##STR158##    No.       R.sup.1         R.sup.2             R.sup.3                    R.sup.4                           X           [α].sub.D.sup.24 ( -c    __________________________________________________________________________                                       1.0)    141       H H   OAc    OAc                            ##STR159## -17.0° (CHCl.sub.3)    142       H H   OAc    OAc                            ##STR160## -11.8° (CHCl.sub.3)    143       H H              ##STR161##                            ##STR162## -30.0° (CHCl.sub.3)    144       H H              ##STR163##                            ##STR164## -30.8° (CHCl.sub.3)    145       H H   OH     H                            ##STR165## -18.8° (CH.sub.3 OH)    146       H H   OH     H                            ##STR166## -23.6° (CH.sub.3 OH)    147       H H              ##STR167##                            ##STR168## -23.2° (CH.sub.3 OH)    148       H H              ##STR169##                            ##STR170## -55.4° (CH.sub.3 OH)    149       H H              ##STR171##                            ##STR172## -29.6° (CH.sub.3 OH)    150       H H              ##STR173##                            ##STR174## -31.4° C. (CH.sub.3 OH)    151       Ac         CHO OCH.sub.2 SCH.sub.3                    OCH.sub.2 SCH.sub.3                           N(CH.sub.3).sub.2                                       -37.2° (CHCl.sub.3)    152       H H   OCH.sub.2 SCH.sub.3                    OCH.sub.2 SCH.sub.3                           N(CH.sub.3).sub.2                                       -34.6° (CHCl.sub.3)    153       H H   OCH.sub.2 SCH.sub.3                    OCH.sub.2 SCH.sub.3                            ##STR175## -32.2° (CH.sub.3 OH)    154       Ac         H   OH     OH                            ##STR176## -41.2° (CH.sub.3 OH)    __________________________________________________________________________

                  TABLE 19(b)    ______________________________________    Com-  NMR spectrum δ value ppm    pound 8-Me    3"-OMe    No.   (s, 3H) (s, 3H)  Others (solvent)    ______________________________________    141   1.59    3.34     1.99 (OAc, s, 3H), 2.03 (OAc, s, 3H)                           2.42 (3'-NMe, s, 3H) (CDCl.sub.3)    142   1.60    3.34     1.99 (OAc, s, 3H), 2.03 (OAc, s, 3H)                           2.23 (3'-NMe, s, 3H) (CDCl.sub.3)    143   1.62    3.35     2.42 (3'-NMe, s, 3H) (CDCl.sub.3)    144   1.61    3.35     2.23 (3'-NMe, s, 3H) (CDCl.sub.3)    145   1.58    3.38     3.14 (3'-NMe.sub.2, s, 6H) (CD.sub.3 OD)    146   1.58    3.39     3.25 (3'-NMe.sub.2, s, 6H) (CD.sub.3 OD)    147   1.62    3.39                            ##STR177##                           3.27 (3'-NMe.sub.2, s, 6H)    148   1.62    3.39     3.28 (3'-NMe.sub.2, s, 6H) (CD.sub.3 OD)                           7.3-7.8 (ph, m, 5H)    149   1.61    3.53     3.37 (3'-NMe.sub.2, s, 6H) (CDCl.sub.3)    150   1.57    3.39     3.39 (3'-NMe.sub.2, s, 6H) (CD.sub.3 OD)    151   1.58    3.36     2.04 (2'-OAc, s, 3H), (CDCl.sub.3)                           2.27 (3'-NMe.sub.2, s, 6H),                           8.19 (4"-CHO, s, 1H)    152   1.58    3.35     2.22 (11-SCH.sub.3, s, 3H), (CDCl.sub.3)                           2.24 (12-SCH.sub.3, s, 3H),                           2.29 (3'-NMe.sub.2, s, 6H)    153   1.58    3.39     2.22 (SCH.sub.3, s, 6H), (CD.sub.3 OD)                           3.25 (3'-NMe.sub.2, s, 6H)    154   1.56    3.38     2.20 (2'-OAc, s, 3H), (CD.sub.3 OD)                           3.32 (3'-NMe.sub.2, s, 6H)    ______________________________________

REFERENCE EXAMPLE 143

150 mg of the compound 84 was dissolved in 3 ml of chloroform, then 0.5ml of propargyl chloride was added thereto and the mixture was heatedunder reflux for 1 day. Thereafter, the same processing as in ReferenceExample 50 was conducted to obtain 142 mg (yield 86%) of9-dihidroerythromycin A 6,9-epoxide propargyl chloride(compound 155) inwhite powder.

REFERENCE EXAMPLE 144

By using 143 mg of the compound 84, 27 ml of acetic anhydride and 31 μlof pyridine, the same processing as in Reference Example 23 wasconducted to obtain 125 mg (yield 83%) of2'-acetyl-9-dihydroerythromycin A 6,9-epoxide (compound 156) in whitepowder.

REFERENCE EXAMPLE 145

150 mg of the compound 84 was dissolved in 3 ml of chloroform, then 0.5ml of benzyl chloride was added thereto and the mixture was heated underreflux for 38 hours. Thereafter, the same processing as in ReferenceExample 50 was conducted to obtain 155 mg (yield 81%) of9-dihidroerythromycin A 6,9-epoxide benzyl chloride (compound 157) inwhite powder.

REFERENCE EXAMPLE 146

150 mg of the compound 84 was dissolved in 3 ml of chloroform, then 0.5ml of 1-bromo-2-fluoroethane was added thereto and the mixture washeated under reflux for 7 days. Thereafter, the same processing as inReference Example 50 was conducted to obtain 66 mg (yield 37%) of9-dihidroerythromycin A 6,9-epoxide 2-fluoroethyl bromide (compound 158)in pale yellow powder.

REFERENCE EXAMPLE 147

150 mg of the compound 84 was dissolved in 3 ml of chloroform, then 0.5ml of cyclopropylmethyl bromide was added thereto and the mixture washeated under reflux for 38 hours. Thereafter, the same processing as inReference Example 50 was conducted to obtain 153 mg (yield 86%) of9-dihidroerythromycin A 6,9-epoxide cyclopropylmethyl bromide (compound159) in white powder.

REFERENCE EXAMPLE 148

150 mg of the compound 84 was dissolved in 3 ml of chloroform, then 0.5ml of 3-butenyl bromide was added thereto and the mixture was heatedunder reflux for 38 hours. Thereafter, the same processing as inReference Example 50 was conducted to obtain 113 mg (yield 63%) of9-dihidroerythromycin A 6,9-epoxide 3-butenyl bromide (compound 160) inwhite powder.

REFERENCE EXAMPLE 149

125 mg of the compound 156 was dissolved in 3 ml of chloroform, then 0.5ml of propargyl bromide was added thereto and the mixture was allowed tostand at room temperature for 3 hours. Thereafter, the same processingas in Reference Example 50 was conducted to obtain 114 mg (yield 79%) of2'-0-acetyl-9-dihidroerythromycin A 6,9-epoxide propargyl bromide(compound 161) in white powder.

The structural formulae, specific rotatory powers and NMR spectrumvalues of the compounds obtained in Reference Examples 143-149 are shownin Table 20.

                                      TABLE 20    __________________________________________________________________________     ##STR178##    Compound                [α].sub.D.sup.24                                     NMR spectrum δ value ppm (CD.sub.3                                     OD)    No.   R  X              ( .sub.-c 1.0, CH.sub.3 OH)                                     3'-NMe.sub.2 (s, 6H)                                             3"-OMe (s, 3H)                                                     Others    __________________________________________________________________________    155   H              ##STR179##    -44.4°                                     3.20    3.37    156   Ac N(CH.sub.3).sub.2                            -53.6°                                     2.28    3.35    2.07 (2'-OAc, s, 3H)                                                     (CDCl.sub.3)    157   H              ##STR180##    -47.4°                                     3.12    3.33    158   H              ##STR181##    -38.4°                                     3.25    3.36    159   H              ##STR182##    -37.0°                                     3.23    3.36    160   H              ##STR183##    -37.6°                                     3.13    3.37    161   Ac              ##STR184##    -52.0°                                     3.23    3.36    2.21 (2'-OAc, s,    __________________________________________________________________________                                                     3H)

REFERENCE EXAMPLE 150

By using 64 mg of 6-0-methylerythromycin A (reference: S. Morimoto, etal., J. Antibiotics, 37, 187, 1984) and 0.1 ml of propargyl bromide, thesame processing as in Reference Example 50 was conducted to obtain 73 mg(yield 98%) of 6-0-methylerythromycin A propargyl bromide (compound 162)in white powder.

REFERENCE EXAMPLE 151

200 mg of erythromycin A was dissolved in 3 ml of chloroform, then 0.3ml of ethyl iodide was added thereto and the mixture was heated underreflux for 20 hours. Thereafter, the same processing as in ReferenceExample 54 was conducted to obtain 150 mg (yield 62%) of erythromycin Aethyl iodide (compound 163) in pale yellow powder.

REFERENCE EXAMPLE 152

100 mg of erythromycin A was dissolved in 2 ml of chloroform, then 0.2ml of allyl bromide was added thereto and the mixture was stirred atroom temperature for 5 hours. Thereafter, the same processing as inReference Example 50 was conducted to obtain 97 mg (yield 83%) oferythromycin A allyl bromide (compound 164) in white powder.

REFERENCE EXAMPLE 153

200 mg of erythromycin A was dissolved in 3 ml of chloroform, then 0.2ml of propargyl bromide was added thereto and the mixture was stirred atroom temperature for 3 hours. Thereafter, the same processing as inReference Example 54 was conducted to obtain 202 mg (yield 87%) oferythromycin A propargyl bromide (compound 165) in white powder.

The structural formulae, specific rotatory powers and NMR spectrumvalues of the compounds obtained in Reference Examples 150-153 are shownin Table 21.

                                      TABLE 21    __________________________________________________________________________     ##STR185##    Compound            [α].sub.D.sup.24                                NMR spectrum δ value ppm (CD.sub.3 OD)    No.   R.sub.1             R.sub.2 X  ( .sub.-c 1.0, CH.sub.3 OH)                                3'-NMe.sub.2 (s, 6H)                                         3"-OMe (s, 3H)                                                Others    __________________________________________________________________________    162   CH.sub.3             CH.sub.2 CCH                     Br -77.4°                                3.26    3.36    3.04 (6-OMe, s, 3H)    163   H  C.sub.2 H.sub.5                     I  -43.6°                                3.20    3.35    164   H  CH.sub.2 CH CH                     Br -50.4°                                3.12    3.35    165   H  CH.sub.2 CCH                     Br -54.6°                                3.27    3.36    __________________________________________________________________________

REFERENCE EXAMPLE 154

50 mg of the compound 9 was dissolved in 1 ml of chloroform, then 0.2 mlof methyl iodide was added thereto and the mixture was stirred at roomtemperature for 3 hours. Thereafter, the same processing as in ReferenceExample 50 was conducted to obtain 49 mg (yield 83%) of4"-0-formyl-8,9-anhydroerythromycin A 6,9-hemiketal methyl iodide(compound 166) in pale yellow powder.

REFERENCE EXAMPLE 155

50 mg of the compound 9 was dissolved in 2 ml of chloroform, then 0.5 mlof ethyl iodide was added thereto and the mixture was heated underreflax for 20 hours. Subsequently, the same processing as in ReferenceExample 50 was conducted to obtain 38 mg (yield 13%) of4"-0-formyl-8,9-anhydroerythromycin A 6,9-hemiketal ethyl iodide(compound 167) in pale yellow powder.

REFERENCE EXAMPLE 156

50 mg of the compound 9 was dissolved in 2 ml of chloroform, then 0.5 mlof propyl iodide was added thereto and the mixture was heated underreflax for 48 hours. Subsequently, the same processing as in ReferenceExample 50 was conducted to obtain 34 mg (yield 56%) of4"-0-formyl-8,9-anhydroerythromycin A 6,9-hemiketal propyl iodide(compound 168) in pale yellow powder.

REFERENCE EXAMPLE 157

50 mg of the compound 9 was dissolved in 1 ml of chloroform, 0.2 ml ofpropargyl bromide was added and the mixture was stirred at roomtemperature for 3 hours. Subsequently, the same processing as inReference Example 50 was conducted to obtain 51 mg (yield 87%) of4"-0-formyl-8,9-anhydroerythromycin A 6,9-hemiketal propargyl bromide(compound 169) in white powder.

REFERENCE EXAMPLE 158

50 mg of the compound 9 was dissolved in 1 ml of chloroform, then 0.2 mlof allyl bromide was added thereto and the mixture was stirred at roomtemperature for 5 hours. Subsequently, the same processing as inReference Example 50 was conducted to obtain 47 mg (yield 80%) of4"-0-formyl-8,9-anhydroerythro- mycin A 6,9-hemiketal allyl bromide(compound 170) in white powder.

REFERENCE EXAMPLE 159

50 mg of the compound 50 was processed in the same manner as inReference Example 154 to obtain 50 mg (yield 84%) of11-0-acetyl-8,9-anhydroerythromycin A 6,9-hemiketal methyl iodide(compound 171) in pale yellow powder.

REFERENCE EXAMPLE 160

50 mg of the compound 50 was processed in the same manner as inReference Example 155 to obtain 39 mg (yield 65%) of11-0-acetyl-8,9-anhydroerythromycin A 6,9-hemiketal ethyl iodide(compound 172) in pale yellow powder.

REFERENCE EXAMPLE 161

50 mg of the compound 50 was processed in the same manner as inReference Example 156 to obtain 33 mg (yield 54%) of11-0-acetyl-8,9-anhydroerythromycin A 6,9-hemiketal propyl iodide(compound 173) in pale yellow powder.

REFERENCE EXAMPLE 162

50 mg of the compound 50 was processed in the same manner as inReference Example 157 to obtain 49 mg (yield 84%) of11-0-acetyl-8,9-anhydroerythromycin A 6,9-hemiketal propargyl bromide(compound 174) in white powder.

REFERENCE EXAMPLE 163

50 mg of the compound 50 was processed in the same manner as inReference Example 162 to obtain 46 mg (yield 79%) of11-0-acetyl-8,9-anhydroerythromycin A 6,9-hemiketal allyl bromide(compound 175) in white powder.

REFERENCE EXAMPLE 164

50 mg of the compound 25 was dissolved in 1 ml of chloroform, then 0.2ml of propargyl bromide was added thereto and the mixture was stirred atroom temperature for 3 hours. Thereafter, the same processing as inReference Example 50 was conducted to obtain 44 mg (yield 77%) of4"-0-formyl-11-0-mesyl-8,9-anhydroerythromycin A 6,9-hemiketal propargylbromide (compound 176) in white powder.

REFERENCE EXAMPLE 165

50 mg of the compound 57 was dissolved in 2 ml of chloroform, then 0.3ml of ethyl iodide was added thereto and the mixture was heated underreflux for 20 hours. Subsequently, the same processing as in ReferenceExample 50 was conducted to obtain 39 mg (yield 66%) of11-0-mesyl-8,9-anhydroerythromycin A 6,9-hemiketal ethyl iodide(compound 177) in pale yellow powder.

REFERENCE EXAMPLE 166

50 mg of the compound 57 was dissolved in 2 ml of chloroform, then 0.3ml of propyl iodide was added thereto and the mixture was heated underreflux for 48 hours. Subsequently, the same processing as in ReferenceExample 54 was conducted to obtain 34 mg (yield 56%) of11-0-mesyl-8,9-anhydroerythromycin A 6,9-hemiketal propyl iodide(compound 178) in pale yellow powder.

The structural formulae, specific rotatory powers and NMR spectrumvalues of the compounds obtained in Reference Examples 154-166 are shownin Table 22.

                                      TABLE 22    __________________________________________________________________________     ##STR186##                                      NMR spectrum δ value ppm                                      (CD.sub.3 OD)    Compound                  [α].sub.D.sup.24                                             3'-NMe.sub.2    No.   R.sub.1              R.sub.2                   R.sub.3 X  ( .sub.-c 1.0, CH.sub.3 OH)                                      8-CH.sub.3 (s, 3H)                                             (s, 6H)                                                  3"-OMe (s,                                                          Others    __________________________________________________________________________    166   CHO H    CH.sub.3                           I  -31.4°                                      1.59   3.31 3.41    8.33                                                          (4"-OCHO, s, 1H)    167   CHO H    C.sub.2 H.sub.5                           I  -31.8°                                      1.59   3.19 3.41    8.31                                                          (4"-OCHO, s, 1H)    168   CHO H    C.sub.3 H.sub.7                           I  -30.4°                                      1.59   3.20 3.40    8.31                                                          (4"-OCHO, s, 1H)    169   CHO H    CH.sub.2 CCH                           Br -34.4°                                      1.59   3.31 3.41    8.31                                                          (4"-OCHO, s, 1H)    170   CHO H    CH.sub.2 CHCH.sub.2                           Br -32.8°                                      1.59   3.18 3.38    8.29                                                          (4"-OCHO, s, 1H)    171   H   COCH.sub.3                   CH.sub.3                           I  -12.0°                                      1.60   3.29 3.38    2.11                                                          (11-OAc, s, 3H)    172   H   COCH.sub.3                   C.sub.2 H.sub.5                           I  -10.0°                                      1.60   3.15 3.38    2.10                                                          (11-OAc, s, 3H)    173   H   COCH.sub.3                   C.sub.3 H.sub.7                           I  -13.4°                                      1.60   3.19 3.38    2.10                                                          (11-OAc, s, 3H)    174   H   COCH.sub.3                   CH.sub.2 CCH                           Br -14.6°                                      1.60   3.27 3.39    2.11                                                          (11-OAc, s, 3H)    175   H   COCH.sub.3                   CH.sub.2 CHCH.sub.2                           Br -12.4°                                      1.60   3.14 3.37    2.10                                                          (11-OAc, s, 3H)    176   CHO SO.sub.2 CH.sub.3                   CH.sub.2 CCH                           Br -28.8°                                      1.61   3.25 3.41    3.30                                                          (10-OMs, s, 3H)                                                          8.30                                                          (4"-OCHO, s, 1H)    177   H   SO.sub.2 CH.sub.3                   C.sub.2 H.sub.5                           I  -26.4°                                      1.60   3.17 3.37    3.24                                                          (11-OMs, s, 3H)    178   H   SO.sub.2 CH.sub.3                   C.sub.3 H.sub.7                           I  -27.8°                                      1.60   3.18 3.37    3.24                                                          (11-OMs, s,    __________________________________________________________________________                                                          3H)

EXAMPLE 1

A capsule preparation is formed by sufficiently mixing the followingcomponents of the following amounts and filling the same in a No. 3capsule:

    ______________________________________    11,12-di-O-acetyl-8,9-anhydroerythro-                              1.5 mg    mycin A-6,9-hemiketal [Compound (32)]    Lactobionic acid          0.75 mg    Lactose                   96.25 mg    Magnesium stearate        1 mg    per capsule               99.5 mg    ______________________________________

For an aduit, 1 to 2 capsules are given three times a day before eachmeal.

EXAMPLE 2

The following components of the following amounts are formed as a flattablet, with slanted edges, of a diameter of 6.5 mm, according to theJapanese Pharmacopoeia, General Rule 14, Tablet Preparation:

    ______________________________________    11,12-di-O-acetyl-8,9-anhydroerythro-                              2.5 mg    mycin A-6,9-hemiketal [Compound (32)]    Lactobionic acid          1.25 mg    Lactose                   72.25 mg    Corn starch               30 mg    Hydroxypropyl cellulose   3 mg    Magnesium stearate        0.5 mg    per tablet                109.5 mg    ______________________________________

For an adult, a tablet is given three times a day before each meal.

EXAMPLE 3

The following components of the following amounts are dissolved indistilled water for injection, then filtered by a Millipore filter, andlyophilized. An intravenous injection preparation is prepared, at use,by dissolving thus lyophilized product in distilled water for injectionto a total volume of 5 ml:

    ______________________________________    11,12-di-O-acetyl-8,9-anhydroerythro-                              2 mg    mycin A-6,9-hemiketal [Compound (32)]    Lactobionic acid          1 mg    Mannitol                  150 mg                              153 mg    ______________________________________

For an adult, this preparation is divided into 10 portions, and threeadministrations are given a day, one portion each time.

EXAMPLE 4

A capsule preparation is formed by sufficiently mixing the followingcomponents of the following amounts and filling the same in a No. 3capsule:

    ______________________________________    11-O-methanesulfonyl-8,9-anhydroery-                              1.5 mg    thromycin A-6,9-hemiketal [Compound (57)]    Lactobionic acid          0.75 mg    Lactose                   96.25 mg    Magnesium stearate        1 mg    per capsule               99.5 mg    ______________________________________

For an adult, 1 to 2 capsules are given three times a day before eachmeal.

EXAMPLE 5

The following components of the following amounts are formed as a flattablet, with slanted edges, of a diameter of 6.5 mm, according to theJapanese Pharmacopoeia, General Rule 14, Tablet Preparation:

    ______________________________________    11-O-methanesulfonyl-8,9-anhydroerythro                              2.5 mg    mycin A-6,9-hemiketal [Compound (57)]    Lactobionic acid          1.25 mg    Lactose                   72.25 mg    Corn starch               30 mg    Hydroxypropyl cellulose   3 mg    Magnesium stearate        0.5 mg    per tablet                109.5 mg    ______________________________________

For an adult, a tablet is given three times a day before each meal.

EXAMPLE 6

The following components of the following amounts are dissolved indistilled water for injection, then filtered by a Millipore filter, andlyophilized. An intravenous injection preparation is prepared, at use,by dissolving thus lyophilized product in distilled water for injectionto a total volume of 5 ml.:

    ______________________________________    11-O-methanesulfonyl-8,9-anhydroerythro-                              2 mg    mycin A-6,9-hemiketal [Compound (57)]    Lactobionic acid          1 mg    Mannitol                  150 mg                              153 mg    ______________________________________

For an adult, this preparation is divided into 10 portions, and threeadministrations are given a day, one portion each time.

EXAMPLE 7

    ______________________________________    8,9-anhydroerythromycin A 6,9-hemiketal-                              0.5 mg    methyliodid [Compound (55)]    Lactose                   96.25 mg    Magnesium stearate        1 mg    per capsule               96.75 mg    ______________________________________

A capsule preparation is formed by sufficiently mixing the abovecomponents of the above amounts and filling the same in a No. 3 capsule.

For an adult, 1 to 2 capsules are given three times a day before eachmeal.

EXAMPLE 8

    ______________________________________    8,9-anhydroerythromycin A-6,9-hemiketal-                             0.2 mg    ethyliodid [Compound (60)]    Lactose                  72.25 mg    Corn starch              30 mg    lHydroxypropyl cellulose 3 mg    Magnesium stearate       0.5 mg    per capsule              105.95 mg    ______________________________________

The above components of the above amounts are formed as a flat table,with slated edges, of a diameter of 6.5 mm, according to the JapanesePharmacopoeia, General Rule 14, Tablet Preparation.

For an adult, a tablet is given three times a day before each meal.

EXAMPLE 9

    ______________________________________    11-O-methanesulfonyl-4"-O-formyl 8,9-                              2.5 mg    anhydroerythromycin A-6,9-hemiketal    [Compound (25)]    Lactobionic acid          1.25 mg    Lactose                   72.25 mg    Corn starch               30 mg    Hydroxypropyl cellulose   3 mg    Magnesium stearate        0.5 mg    per capsule               109.5 mg    ______________________________________

The above components of the above amounts are formed as a flat table,with slanted edges, of a diameter of 6.5 mm, according to the JapanesePharmacopoeia, General Rule 14, Tablet Preparation.

For an adult, a tablet is given three times a day before each meal.

As described hereinbefore, the compound [1] has an excellent effect ofstimulating the gastrointenstinal contractive motion, and thepreparation of the present invention containing this compound can beadvantageously used as a digestive tract contractile motion stimulant.

What is claimed is:
 1. A therapeutic method of stimulating digestivetract contractile motion in mammals which comprises administering orallyor non-orally to mammals in need of such treatment an effective amountof a digestive tract contractile motion stimulant composition comprisinga pharmaceutically acceptable carrier and an effective digestivecontractile motion stimulating amount of a compound having the formula:##STR187## wherein R¹ is selected from the group consisting of: ahydrogen atom,an acyl radical of C₁₋₅ aliphatic carboxylic acid, a C₆₋₁₂aroyl radical, a C₁₋₆ alkylsulfonyl radical, a C₂₋₁₂dialkyloxyphosphoryl radical, and a C₁₂₋₂₄ diaryloxyphosphoryl radical;R² is selected from the group consisting of: a hydrogen atom, a C₁₋₆alkanoyl radical which may be substituted by C₁₋₃ alkoxycarbonylradical, a C₆₋₁₂ aroyl radical, a C₁₋₆ alkylsulfonyl radical, a C₆₋₁₂arylsulfonyl radical, a C₇₋₂₀ aralkylsulfonyl radical, and a C₁₋₃ alkylradical which may be substituted by C₂₋₆ alkoxy radical; wherein Zstands for the formula: ##STR188## where in R⁵ is selected from thegroup consisting of: a hydrogen atom, a C₁₋₆ alkanoyl radical, a C₆₋₁₂aroyl radical, a C₁₋₆ alkylsulfonyl radical, a C₆₋₁₂ arylsulfonylradical, a C₇₋₂₀ aralkylsulfonyl radical, and a C₁₋₃ alkyl radical whichmay be substituted by C1-4 alkylthio radical, and R⁶ is selected fromthe group consisting of: a hydrogen atom, a C₁₋₆ alkanoyl radical; and aC₁₋₃ alkyl radical which may be unsubstituted by C₁₋₄ alkylthio radical,or wherein Z stands for the formula: ##STR189## or Z stands for the forthe formula: ##STR190## wherein Y stands for the formula B-R⁸ (whereinR⁸ stands for C₆₋₁₂ aryl radical) ##STR191## or the formula: ##STR192##wherein each of R⁹ and R¹⁰, which may e the same or different, standsfor a hydrogen atom or a C₁₋₆ alkyl radical; ##STR193## wherein R^(b) isselected from the group consisting of: a hydrogen atom and a C₁₋₆ alkylradical; and wherein R^(c) is selected from the group consisting of: ahydrogen atom, a C₂₋₆ alkyl radical which may be substituted with one ormore hydroxyl radicals, a C₂₋₆ alkenyl radical, and a C₂₋₆ alkynylradical; or together R^(b) and R^(c) from a C₃₋₆ cyclic alkylaminoradical together with the adjacent nitrogen atom; or R^(a) stands forthe formula ##STR194## wherein R^(d) is a C₁₋₆ alkyl radical, and R^(e)and R^(f), which may be the same or different are selected from thegroup consisting of: a hydrogen atom, a C₁₋₆ alkyl radical which may besubstituted by hydroxyl radical, carboxy radical, cyano radical, orhalogen, a C₃₋₅ cycloalkyl radical, or a C₁₋₃ alkoxycarbonyl radical; aC₇₋₂₀ aralkyl radical; a C₂₋₆ alkenyl radical; and a C₂₋₆ alkynylradical; or together R^(e) and R^(f) form a C₅₋₇ cyclic alkylaminoradical with the adjacent nitrogen atom; X stands for an anion; and R¹¹and R¹² each represent a hydrogen atom or both taken together form achemical bond.
 2. The method of claim 1, wherein the digestive tractcontractile motion stimulant compound is selected from the groupconsisting of: 8,9-anhydroerythromycin A 6,9-hemiketal methyl iodide,8,9-anhydroerythromycin A 6,9-hemiketal 2-hydroxyethyl bromide,8,9-anhydfroerythromycin A 6,9-hemiketal allyl bromide,8,9-anhydroerythromycin A 6,9-hemiketal benzyl chloride,8,9-anhydroerythromycin A 6,9-hemiketal ethyl bromide,diethyl-dinor-anhydroerythromycin A 6,9-hemiketal,8,9-anhydroerythromycin A propargyl bromide,allyl-nor-8,9-anhydroerythromycin A 6,9-hemiketal and8,9-anhydroerythromycin A 6,9-hemiketal propargyl chloride.
 3. Themethod of claim 1, wherein R¹ in the digestive tract contractile motionstimulant compound is a hydrogen atom or an acyl radical of C₁₋₅aliphatic carboxylic acid.
 4. The method of claim 1, wherein R² in thedigestive tract contractile motion stimulant compound is a hydrogenatom, a C₁₋₅ alkanoyl radical or C₁₋₅ alkylsulfonyl radical.
 5. Themethod of claim 1, wherein Z in the digestive tract contractile motionstimulant compound has the formula: ##STR195## wherein each of R₅ and R₆are independently selected from the group consisting of hydrogen atom,and a C₁₋₅ alkanoyl radical.
 6. The method of claim 1, wherein Y in thedigestive tract contractile motion stimulant compound is selected fromthe group consisting of: ##STR196##
 7. The method of claim 1, whereinR^(a) in the digestive tract contractile motion stimulant compound hasthe formula: ##STR197## wherein R^(b) is a C₁ to C₆ radical and R^(c) isa C₂ to C₆ alkyl radical which may be substituted with one or morehydroxyl radicals.
 8. The method of claim 1, wherein R^(a) in thedigestive tract contractile motion stimulant compound isN-methyl-N-ethylamino radical.
 9. The method of claim 1, wherein R^(a)in the digestive tract contractile motion stimulant compound has theformula: ##STR198## wherein R^(d) is a C₁₋₆ alkyl radical, and R^(e) andR^(f), which may be the same or different are selected from the groupconsisting of:a hydrogen atom, a C₁₋₆ alkyl radical which may besubstituted by hydroxyl radical, carboxy radical, cyano radical,halogen, C₃₋₅ cycloalkyl radical, or C₁₋₃ alkoxycarbonyl radical; aC₇₋₂₀ aralkyl radical; a C₂₋₆ alkenyl radical; and a C₂₋₆ alkynylradical; or together R^(e) and R^(f) form a C₅₋₇ cyclic alkylaminoradical with the adjacent nitrogen atom; and X stands for an anion. 10.THe method of claim 1, wherein R^(f) in the digestive tract contractilemotion stimulant compound is C₂₋₆ alkenyl or C₂₋₆ alkynyl radical. 11.The method of claim 1, wherein R^(e) and R^(f) form a C₅₋₇ cyclicalkylamino radical with the adjacent nitrogen atom.
 12. The method ofclaim 1, wherein a digestive tract contractile motion stimulantcomposition additionally comprises one or more of the pharmaceuticallyacceptable additional components selected from the group consisting ofvehicle, disintegrator, lubricant, binder, dispersant and plasticizer.13. The method of claim 1, wherein the effective amount of the digestivecontractile motion stimulating compound of formula (1) for oraladministration to a mammal in need of such treatment is in the range offrom about 0.0001 to 100 mg/kg in a form diluted or compounded withpharmaceutically acceptable carries or diluents.
 14. The method of claim1, wherein the effective amount of the digestive contractile motionstimulating compound for oral administration to a mammal in need of suchtreatment is in the range of from about 0.00001 to 10 mg/kg in a formdiluted or compounded with pharmaceutically acceptable carriers ordiluents.